1. |
- Fickert, Peter, et al.
(författare)
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Characterization of animal models for primary sclerosing cholangitis (PSC).
- 2014
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 60:6, s. 1290-1303
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Forskningsöversikt (refereegranskat)abstract
- Primary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The International Primary Sclerosing Cholangitis Study Group (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC.
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2. |
- Marschall, Hanns-Ulrich, 1954, et al.
(författare)
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When bile acids don't get amidated.
- 2013
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 144:5, s. 870-3
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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3. |
- Nevens, Frederik, et al.
(författare)
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A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis.
- 2016
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Ingår i: The New England journal of medicine. - 1533-4406. ; 375:7, s. 631-43
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Tidskriftsartikel (refereegranskat)abstract
- Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease.
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4. |
- Nuñez Durán, Esther, et al.
(författare)
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Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice.
- 2018
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Ingår i: Hepatology communications. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 2:1, s. 69-83
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty-first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting Stk25 on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that Stk25 ASOs efficiently reversed high-fat diet-induced systemic hyperglycemia and hyperinsulinemia, improved whole-body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, Stk25 ASOs suppressed the abundance of liver acetyl-coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single-nucleotide polymorphisms in the human STK25 gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. Conclusion: Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. (Hepatology Communications 2018;2:69-83).
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5. |
- Abdel-Khalik, Jonas, et al.
(författare)
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Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.
- 2021
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 206
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography - mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.
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6. |
- Abu-Hayyeh, Shadi, et al.
(författare)
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Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype.
- 2013
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 57:2, s. 716-726
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Tidskriftsartikel (refereegranskat)abstract
- Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP, leading us to study the impact of sulfated progesterone metabolites on farnesoid X receptor (FXR)-mediated bile acid homeostasis pathways. Here we report that the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, coadministration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR, resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using cofactor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of cofactor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis. (HEPATOLOGY 2012;).
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7. |
- Abu-Hayyeh, S., et al.
(författare)
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Prognostic and Mechanistic Potential of Progesterone Sulfates in Intrahepatic Cholestasis of Pregnancy and Pruritus Gravidarum
- 2016
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 63:4, s. 1287-1298
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Tidskriftsartikel (refereegranskat)abstract
- A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice. Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP.
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8. |
- Al-Dury, Samer, et al.
(författare)
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Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH
- 2018
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids are synthesized from cholesterol in the liver, excreted with bile into the duodenum, almost completely taken up again in the distal ileum and finally returned to the liver with portal blood in a process termed enterohepatic circulation. Bile acid synthesis, excretion, and reuptake are tightly regulated. The apical sodium-dependent bile acid transporter [ASBT; also known as ileal bile acid transporter (IBAT) and SLC10A2] is pivotal for the almost complete reabsorption of conjugated bile acids in the ileum. Dysfunctional IBAT may be the cause of bile acid diarrhea. Pharmacological IBAT inhibition results in an increased bile acid load in the colon and subsequently a lower bile acid pool, which is associated with improved liver histology in animal models of cholestatic liver disease and non-alcoholic steatohepatitis (NASH). In humans, IBAT inhibitors have been tested in clinical trials with widely different indications: in patients with idiopathic chronic constipation, an increased number of bowel movements was observed. In adult and pediatric cholestatic liver diseases with pruritus, various IBAT inhibitors showed potential to improve itching. Adverse events of IBAT inhibitors, based on their mode of action, are abdominal pain and diarrhea which might patients to withdraw from study medications. So far, no data are available of a study of IBAT inhibitors in patients with NASH. In this review we summarize the preclinical and most recent clinical studies with various IBAT inhibitors and discuss the difficulties that should be addressed in future studies.
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9. |
- Al-Dury, Samer, et al.
(författare)
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Obeticholic acid may increase the risk of gallstone formation in susceptible patients.
- 2019
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 71:5, s. 986-991
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has been developed for the treatment of liver diseases. We aimed to determine whether OCA treatment increases the risk of gallstone formation.Twenty patients awaiting laparoscopic cholecystectomy were randomized to treatment with OCA (25 mg/day) or placebo for three weeks before surgery. Serum bile acids (BAs), the BA synthesis marker C4 (7α-hydroxy-cholest-4-ene-3-one), and fibroblast growth factor 19 (FGF19) were measured before and after treatment. During surgery, biopsies from the liver and the whole bile-filled gallbladder were collected for analyses of gene expression, biliary lipids and FGF19.In serum, OCA increased FGF19 (from 95.0±8.5 to 234.4±35.6 ng/L) and decreased C4 (from 31.4±22.8 to 2.8±4.0 nmol/L) and endogenous BAs (from 1312.2±236.2 to 517.7±178.9 nmol/L; all p<0.05). At surgery, BAs in gallbladder bile were lower in OCA patients than controls (OCA, 77.9±53.6 mmol/L; placebo, 196.4±99.3 mmol/L; p<0.01), resulting in a higher cholesterol saturation index (OCA, 2.8±1.1; placebo, 1.8±0.8; p < 0.05). In addition, hydrophobic OCA conjugates accounted for 13.6±5.0% of gallbladder BAs after OCA treatment, resulting in a higher hydrophobicity index (OCA, 0.43±0.09; placebo, 0.34±0.07, p<0.05). Gallbladder FGF19 was three-fold higher in OCA patients than in controls (OCA, 40.3±16.5 ng/L; placebo, 13.5±13.1 ng/mL; p<0.005). Gene expression analysis indicated a mainly gallbladder epithelial origin of FGF19.Our results show for the first time an enrichment of FGF19 in human bile after OCA treatment. In accordance with its murine homolog FGF15, FGF19 might trigger relaxation and filling of the gallbladder which, in combination with increased cholesterol saturation and BA hydrophobicity, would enhance the risk for gallstone development.Obeticholic acid increased human gallbladder cholesterol saturation and bile acid hydrophobicity, both decreasing cholesterol solubility in bile. Together with increased hepatobiliary FGF19, our findings suggest that pharmacological FXR activation increases the risk of gallstone formation.
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10. |
- Al-Dury, Samer, et al.
(författare)
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Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Pruritus is a common complication of cholestatic liver diseases. Inhibition of the ileal bile acid transporter (IBAT/ASBT) may emerge as treatment option. Our aim was to assess tolerability and effect on pruritus of the selective IBAT inhibitor A4250 in patients with primary biliary cholangitis (PBC). Ten patients with PBC and bile acid sequestrant treatment of cholestatic pruritus were after a two-week wash out of the bile acid sequestrant treated with either 0.75 mg (n = 4) or 1.5 mg (n = 5) of A4250 for four weeks. Patients' pruritus was assessed by Visual Analogue Scale (VAS), 5-D itch scale and the pruritus module of the PBC40 questionnaire. Plasma bile acids and 7 alpha-hydroxy-4-cholesten-3-one were measured by UPLC-MS/MS, plasma fibroblast growth factor 19 by ELISA, and serum autotaxin activity by homemade assay. All nine patients exposed to A4250 reported a remarkable improvement in pruritus, until none or mild according to 5-D itch, VAS and PBC40 pruritus. Five patients finished the study prematurely due to abdominal pain (5/5) and diarrhoea (4/5). The high incidence of probably bile acid malabsorption-related diarrhoea and abdominal pain in the bile acid sequestrant pre-treated population indicates that the start dose of A4250 may have been too high for adult patients.
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11. |
- Alberts, R, et al.
(författare)
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Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
- 2018
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:8, s. 1517-1524
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Tidskriftsartikel (refereegranskat)abstract
- Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.DesignWe collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.ConclusionWe present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.
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12. |
- Amrutkar, Manoj, et al.
(författare)
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STK25 is a critical determinant in nonalcoholic steatohepatitis.
- 2016
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - 1530-6860. ; 30:10, s. 3628-3643
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and 10-20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH) with a high risk of cirrhosis, liver failure, and hepatocellular carcinoma. Despite its high medical importance, the molecular mechanisms controlling progression from simple liver steatosis to NASH remain elusive. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid deposition, systemic glucose, and insulin homeostasis. To elucidate the role of STK25 in the development of NASH, we challenged Stk25-knockout and transgenic mice with a methionine and choline-deficient (MCD) diet. We show that Stk25(-/-) mice are protected against MCD-diet-induced NASH, as evidenced by repressed liver steatosis, oxidative damage, inflammation, and fibrosis, whereas Stk25 transgenic mice developed a more severe NASH phenotype, compared with corresponding wild-type littermates. Consistently, NASH features were suppressed in STK25-deficient human hepatocytes cultured in MCD medium, and reciprocally enhanced in STK25-overexpressing cells. We also found a significant positive correlation in human liver biopsies between STK25 expression and NASH development. The study provides evidence for multiple roles of STK25 in NASH pathogenesis and future investigations to address the potential therapeutic relevance of pharmacological STK25 inhibitors in prevention and treatment of NASH are warranted.-Amrutkar, M., Chursa, U., Kern, M., Nuñez-Durán, E., Ståhlman, M., Sütt, S., Borén, J., Johansson, B. R., Marschall, H.-U., Blüher, M., Mahlapuu, M. STK25 is a critical determinant in nonalcoholic steatohepatitis.
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13. |
- Baghdasaryan, A., et al.
(författare)
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Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis
- 2016
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278. ; 64:3, s. 674-681
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury. Methods: Eight week old Mdr2(-/-) (Abcb4(-/-)) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.01% w/w) - a highly potent and selective ASBT inhibitor - or a chow diet. Liver injury was assessed biochemically and histologically after 4 weeks of A4250 treatment. Expression profiles of genes involved in BA homeostasis, inflammation and fibrosis were assessed via RT-PCR from liver and ileum homogenates. Intestinal inflammation was assessed by RNA expression profiling and immunohistochemistry. Bile flow and composition, as well as biliary and fecal BA profiles were analyzed after 1 week of ASBT inhibitor feeding. Results: A4250 improved sclerosing cholangitis in Mdr2(-/-) mice and significantly reduced serum alanine aminotransferase, alkaline phosphatase and BAs levels, hepatic expression of proinflammatory (Tnf-alpha, Vcam1, Mcp-1) and pro-fibrogenic (Col1a1, Col1a2) genes and bile duct proliferation (mRNA and immunohistochemistry for cytokeratin 19 (CK19)). Furthermore, A4250 significantly reduced bile flow and biliary BA output, which correlated with reduced Bsep transcription, while Ntcp and Cyp7a1 were induced. Importantly A4250 significantly reduced biliary BA secretion but preserved HCO3- and biliary phospholipid secretion resulting in an increased HCO3-/BA and PL/BA ratio. In addition, A4250 profoundly increased fecal BA excretion without causing diarrhea and altered BA pool composition, resulting in diminished concentrations of primary BAs tauro-beta-muricholic acid and taurocholic acid. Conclusions: Pharmacological ASBT inhibition attenuates cholestatic liver and bile duct injury by reducing biliary BA concentrations in mice. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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14. |
- Baldaque-Silva, F., et al.
(författare)
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Impact of gastroesophageal reflux control through tailored proton pump inhibition therapy or fundoplication in patients with Barrett's esophagus
- 2017
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327 .- 2219-2840. ; 23:17, s. 3174-3183
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Tidskriftsartikel (refereegranskat)abstract
- AIM To determine the impact of upwards titration of proton pump inhibition (PPI) on acid reflux, symptom scores and histology, compared to clinically successful fundoplication. Two cohorts of long-segment Barrett's esophagus (BE) patients were studied. In group 1 (n = 24), increasing doses of PPI were administered in 8-wk intervals until acid reflux normalization. At each assessment, ambulatory 24 h pH recording, endoscopy with biopsies and symptom scoring (by a gastroesophageal reflux disease health related quality of life questionnaire, GERD/HRLQ) were performed. Group 2 (n = 30) consisted of patients with a previous fundoplication. In group 1, acid reflux normalized in 23 of 24 patients, resulting in improved GERD/HRQL scores (P = 0.001), which were most pronounced after the starting dose of PPI (P < 0.001). PPI treatment reached the same level of GERD/HRQL scores as after a clinically successful fundoplication (P = 0.5). Normalization of acid reflux in both groups was associated with reduction in papillary length, basal cell layer thickness, intercellular space dilatation, and acute and chronic inflammation of squamous epithelium. This study shows that acid reflux and symptom scores co-vary throughout PPI increments in long-segment BE patients, especially after the first dose of PPI, reaching the same level as after a successful fundoplication. Minor changes were found among GERD markers at the morphological level.
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15. |
- Bellafante, E., et al.
(författare)
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Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic beta-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect beta-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr(-/-) and Tgr5(-/-) mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr(-/-) mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr(-/-) mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.
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16. |
- Biemann, R., et al.
(författare)
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Serum bile acids and GLP-1 decrease following telemetric induced weight loss: results of a randomized controlled trial
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids (BAs) are increasingly recognised as metabolic regulators, potentially improving insulin sensitivity following bariatric surgery. However, physiological relevance of such observations remains unknown. Hence, we analysed serum BA composition and associated gut-derived hormone levels following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). 74 non-smoking men (45-55 yr) with MetS were randomised to a lifestyle-induced weight loss program (supervision via telemonitoring) or to a control arm. Before and after a 6 months intervention period clinical and laboratory parameters, body composition, serum BA profile, FGF-19, and GLP-1 concentrations were determined in fasting blood samples. 30 participants in the control and 33 participants in the treatment arm completed the study and were included in the data analysis. In participants of the treatment arm lifestyle-induced weight loss resulted in markedly improved insulin sensitivity. Serum levels of BA species and total GLP-1 decreased, while FGF-19 remained stable. Serum BA composition changed towards an increased 12 alpha-hydroxylated/non-12 alpha-hydroxylated ratio. None of these parameters changed in participants of the control arm. Our results demonstrate that improved metabolic control by lifestyle modifications lowers serum levels of BAs and GLP-1 and changes serum BA composition towards an increased 12 alpha/non-12 alpha ratio (ICTRP Trial Number: U1111-1158-3672).
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17. |
- Borges Manna, Luiza, et al.
(författare)
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Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy.
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Perturbations in the intrauterine environment can result in lifelong consequences for metabolic health during postnatal life. Intrahepatic cholestasis of pregnancy (ICP) can predispose offspring to metabolic disease in adulthood, likely due to a combination of the effects of increased bile acids, maternal dyslipidemia and deranged maternal and fetal lipid homeostasis. Whereas ursodeoxycholic acid (UDCA) is a commonly used treatment for ICP, no studies have yet addressed whether it can also prevent the metabolic effects of ICP in the offspring and fetoplacental unit. We therefore analyzed the lipid profile of fetal serum from untreated ICP, UDCA-treated ICP and uncomplicated pregnancies and found that UDCA ameliorates ICP-associated fetal dyslipidemia. We then investigated the effects of UDCA in a mouse model of hypercholanemic pregnancy and showed that it induces hepatoprotective mechanisms in the fetal liver, reduces hepatic fatty acid synthase (Fas) expression and improves glucose tolerance in the adult offspring. Finally, we showed that ICP leads to epigenetic changes in pathways of relevance to the offspring phenotype. We therefore conclude that UDCA can be used as an intervention in pregnancy to reduce features of metabolic disease in the offspring of hypercholanemic mothers.
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18. |
- Borssen, A. D., et al.
(författare)
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Histological improvement of liver fibrosis in well-treated patients with autoimmune hepatitis A cohort study
- 2017
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Ingår i: Medicine (United States). - : Ovid Technologies (Wolters Kluwer Health). - 0025-7974. ; 96:34
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune hepatitis (AIH) is a chronic autoimmune liver disease that if left untreated may lead to the development of cirrhosis. Previous studies on AIH patients have suggested that fibrosis and even cirrhosis can be reversed by medical treatment. The aim of this study was to evaluate the efficacy of medical treatment for protection of developing fibrosis and cirrhosis. A total of 258 liver biopsies from 101 patients (72 women, 29 men) were analyzed by a single pathologist and classified according to the Ishak grading (inflammation) and staging (fibrosis) system. Liver histology was stratified according to the temporal changes of fibrosis stage (increased, decreased, or stable), and groups were compared. Complete or partial response to medical treatment was 94.9%. Reduction of fibrosis stage from the first to the last biopsy was seen in 63 patients (62.4%). We found an association between a reduction in the fibrosis stage and continuous glucocorticoid medication, as well as lowered scores of inflammation at last biopsy. Twenty-one patients had cirrhosis (Ishak stage 6) at least in one of the previous biopsies, but only 5 patients at the last biopsy. Histological improvement is common in AIH patients that respond to medical treatment, and a reduction or stabilization of fibrosis stage occurs in about 2/3 of such patients.
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19. |
- Braadland, P. R., et al.
(författare)
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Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis
- 2022
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Ingår i: Jhep Reports. - : Elsevier BV. - 2589-5559. ; 4:11
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy.Methods: Concentrations of individual bile acids and 7a-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort. Results: The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06-1.43) and validation (adjusted HR = 1.23, 95% CI 1.03-1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis.Conclusions: Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation.Lay summary: We show, by measuring the level of the metabolite C4 in the blood from patients with primary sclerosing cholangitis (PSC), that low production of bile acids in the liver predicts a more rapid progression to severe disease. Many people with PSC appear to have fully suppressed bile acid production, and both established and new drugs that aim to reduce bile acid production may therefore be futile for them. We propose C4 as a test to find those likely to respond to these treatments.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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20. |
- Burza, M. A., et al.
(författare)
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The 35-year odyssey of beta blockers in cirrhosis: any gender difference in sight?
- 2017
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618. ; 119, s. 20-26
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Tidskriftsartikel (refereegranskat)abstract
- Cirrhosis is the end-stage of chronic liver disease and leads to the development of portal hypertension and its complications such as esophagogastric varices. Non-selective beta blockers (NSBB) are the keystone for the treatment of portal hypertension since the 1980s and, over the decades, several studies have confirmed their beneficial effect on the prevention of variceal (re)bleeding. Pharmacological studies showed effects of gender, sex hormones, oral contraceptives, and pregnancy on cytochrome P450 (CYPs) enzymes that metabolise NSBB, suggesting that gender differences might exist in the effect of NSBB. In this review, we focused on the 35-year knowledge about the use of beta blockers in cirrhosis and potential gender differences. We specifically examined the role of NSBB in pre-primary, primary and secondary prophylaxis of variceal bleeding, compared two commonly used NSBB (i.e., Propranolol and Carvedilol), and present the current controversies about the window of treatment in advanced cirrhosis with a specific focus on gender differences in NSBB effects. NSBB are not currently recommended in pre-primary prophylaxis of varices mainly because of lack of proven efficacy. On the other hand, NSBB are strongly recommended in patient with cirrhosis as primary (as alternative to endoscopic band ligation, EBL) and secondary prophylaxis (in addition to EBL) of variceal bleeding. To date, no studies have focused specifically on the effect of gender on NSBB treatment Data extrapolated from clinical studies show that gender was neither a risk factor for the development of varices nor associated with a different response to treatment in primary or secondary prophylaxis. According to the available guidelines, no different, gender-based treatment for portal hypertension is recommended. (C) 2017 Elsevier Ltd. All rights reserved.
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21. |
- Cansby, Emmelie, 1984, et al.
(författare)
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Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease.
- 2020
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Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:24
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease (DKD) is the most common cause of severe renal disease worldwide and the single strongest predictor of mortality in diabetes patients. Kidney steatosis has emerged as a critical trigger in the pathogenesis of DKD; however, the molecular mechanism of renal lipotoxicity remains largely unknown. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid storage in several metabolic organs prone to diabetic damage. Here, we demonstrate that overexpression of STK25 aggravates renal lipid accumulation and exacerbates structural and functional kidney injury in a mouse model of DKD. Reciprocally, inhibiting STK25 signaling in mice ameliorates diet-induced renal steatosis and alleviates the development of DKD-associated pathologies. Further, we find that STK25 silencing in human kidney cells protects against lipid deposition as well as oxidative and endoplasmic reticulum stress. Together, our results suggest that STK25 regulates a critical node governing susceptibility to renal lipotoxicity and that STK25 antagonism could mitigate DKD progression.
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22. |
- Cansby, Emmelie, 1984, et al.
(författare)
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Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans.
- 2019
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - 1530-6860. ; 33:9, s. 9974-9989
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Tidskriftsartikel (refereegranskat)abstract
- Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepatitis (NASH). Understanding the molecular networks controlling hepatocellular lipid deposition is therefore essential for developing new strategies to effectively prevent and treat this complex disease. Here, we describe a new regulator of lipid partitioning in human hepatocytes: mammalian sterile 20-like (MST) 3. We found that MST3 protein coats lipid droplets in mouse and human liver cells. Knockdown of MST3 attenuated lipid accumulation in human hepatocytes by stimulating β-oxidation and triacylglycerol secretion while inhibiting fatty acid influx and lipid synthesis. We also observed that lipogenic gene expression and acetyl-coenzyme A carboxylase protein abundance were reduced in MST3-deficient hepatocytes, providing insight into the molecular mechanisms underlying the decreased lipid storage. Furthermore, MST3 expression was positively correlated with key features of NASH (i.e., hepatic lipid content, lobular inflammation, and hepatocellular ballooning) in human liver biopsies. In summary, our results reveal a role of MST3 in controlling the dynamic metabolic balance of liver lipid catabolism vs. lipid anabolism. Our findings highlight MST3 as a potential drug target for the prevention and treatment of NASH and related complex metabolic diseases.
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23. |
- Cansby, Emmelie, 1984, et al.
(författare)
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Silencing of STE20-type kinase STK25 in human aortic endothelial and smooth muscle cells is atheroprotective
- 2022
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies highlight the importance of lipotoxic damage in aortic cells as the major pathogenetic contributor to atherosclerotic disease. Since the STE20-type kinase STK25 has been shown to exacerbate ectopic lipid storage and associated cell injury in several metabolic organs, we here investigate its role in the main cell types of vasculature. We depleted STK25 by small interfering RNA in human aortic endothelial and smooth muscle cells exposed to oleic acid and oxidized LDL. In both cell types, the silencing of STK25 reduces lipid accumulation and suppresses activation of inflammatory and fibrotic pathways as well as lowering oxidative and endoplasmic reticulum stress. Notably, in smooth muscle cells, STK25 inactivation hinders the shift from a contractile to a synthetic phenotype. Together, we provide several lines of evidence that antagonizing STK25 signaling in human aortic endothelial and smooth muscle cells is atheroprotective, highlighting this kinase as a new potential therapeutic target for atherosclerotic disease.
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24. |
- Cansby, Emmelie, 1984, et al.
(författare)
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STK25 Regulates Cardiovascular Disease Progression in a Mouse Model of Hypercholesterolemia
- 2018
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Ingår i: Arteriosclerosis Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 38:8, s. 1723-1737
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Tidskriftsartikel (refereegranskat)abstract
- Objective Recent cohort studies have shown that nonalcoholic fatty liver disease (NAFLD), and especially nonalcoholic steatohepatitis (NASH), associate with atherosclerosis and cardiovascular disease, independently of conventional cardiometabolic risk factors. However, the mechanisms underlying the pathophysiological link between NAFLD/NASH and cardiovascular disease still remain unclear. Our previous studies have identified STK25 (serine/threonine protein kinase 25) as a critical determinant in ectopic lipid storage, meta-inflammation, and progression of NAFLD/NASH. The aim of this study was to assess whether STK25 is also one of the mediators in the complex molecular network controlling the cardiovascular disease risk. Approach and Results Atherosclerosis was induced in Stk25 knockout and transgenic mice, and their wild-type littermates, by gene transfer of gain-of-function mutant of PCSK9 (proprotein convertase subtilisin/kexin type 9), which induces the downregulation of hepatic LDLR (low-density lipoprotein receptor), combined with an atherogenic western-type diet. We found that Stk25(-/-) mice displayed reduced atherosclerosis lesion area as well as decreased lipid accumulation, macrophage infiltration, collagen formation, and oxidative stress in aortic lesions compared with wild-type littermates, independently from alterations in dyslipidemia. Reciprocally, Stk25 transgenic mice presented aggravated plaque formation and maturation compared with wild-type littermates despite similar levels of fasting plasma cholesterol. We also found that STK25 protein was expressed in all layers of the aorta, suggesting a possible direct role in cardiovascular disease. Conclusions This study provides the first evidence that STK25 plays a critical role in regulation of cardiovascular disease risk and suggests that pharmacological inhibition of STK25 function may provide new possibilities for prevention/treatment of atherosclerosis.
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25. |
- Caputo, Mara, et al.
(författare)
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Silencing of STE20-type kinase MST3 in mice with antisense oligonucleotide treatment ameliorates diet-induced nonalcoholic fatty liver disease
- 2021
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Ingår i: FASEB Journal. - 0892-6638. ; 35:5
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is emerging as a leading cause of chronic liver disease worldwide. Despite intensive nonclinical and clinical research in this field, no specific pharmacological therapy is currently approved to treat NAFLD, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies have identified STE20-type kinase MST3, which localizes to intracellular lipid droplets, as a critical regulator of ectopic fat accumulation in human hepatocytes. Here, we explored whether treatment with Mst3-targeting antisense oligonucleotides (ASOs) can promote hepatic lipid clearance and mitigate NAFLD progression in mice in the context of obesity. We found that administration of Mst3-targeting ASOs in mice effectively ameliorated the full spectrum of high-fat diet-induced NAFLD including liver steatosis, inflammation, fibrosis, and hepatocellular damage. Mechanistically, Mst3 ASOs suppressed lipogenic gene expression, as well as acetyl-CoA carboxylase (ACC) protein abundance, and substantially reduced lipotoxicity-mediated oxidative and endoplasmic reticulum stress in the livers of obese mice. Furthermore, we found that MST3 protein levels correlated positively with the severity of NAFLD in human liver biopsies. In summary, this study provides the first in vivo evidence that antagonizing MST3 signaling is sufficient to mitigate NAFLD progression in conditions of excess dietary fuels and warrants future investigations to assess whether MST3 inhibitors may provide a new strategy for the treatment of patients with NAFLD.
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26. |
- Caputo, Mara, et al.
(författare)
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STE20-type kinases MST3 and MST4 promote the progression of hepatocellular carcinoma: Evidence from human cell culture and expression profiling of liver biopsies
- 2023
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Ingår i: Faseb Journal. - 0892-6638. ; 37:8
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is one of the most fatal and fastest growing malignancies. Recently, nonalcoholic steatohepatitis (NASH), characterized by liver steatosis, inflammation, cell injury (hepatocyte ballooning), and different stages of fibrosis, has emerged as a major catalyst for HCC. Because the STE20-type kinases, MST3 and MST4, have been described as critical molecular regulators of NASH pathophysiology, we here focused on determining the relevance of these proteins in human HCC. By analyzing public datasets and in-house cohorts, we found that hepatic MST3 and MST4 expression was positively correlated with the incidence and severity of HCC. We also found that the silencing of both MST3 and MST4, but also either of them individually, markedly suppressed the tumorigenesis of human HCC cells including attenuated proliferation, migration, invasion, and epithelial-mesenchymal transition. Mechanistic investigations revealed lower activation of STAT3 signaling in MST3/MST4-deficient hepatocytes and identified GOLGA2 and STRIPAK complex as the binding partners of both MST3 and MST4. These findings reveal that MST3 and MST4 play a critical role in promoting the progression of HCC and suggest that targeting these kinases may provide a novel strategy for the treatment of liver cancer.
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27. |
- Caputo, Mara, et al.
(författare)
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STE20-Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes
- 2021
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Ingår i: Hepatology Communications. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 5:7, s. 1183-1200
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide, primarily because of the massive global increase in obesity. Despite intense research efforts in this field, the factors that govern the initiation and subsequent progression of NAFLD are poorly understood, which hampers the development of diagnostic tools and effective therapies in this area of high unmet medical need. Here we describe a regulator in molecular pathogenesis of NAFLD: STE20-type protein kinase MST4. We found that MST4 expression in human liver biopsies was positively correlated with the key features of NAFLD (i.e., hepatic steatosis, lobular inflammation, and hepatocellular ballooning). Furthermore, the silencing of MST4 attenuated lipid accumulation in human hepatocytes by stimulating beta-oxidation and triacylglycerol secretion, while inhibiting fatty acid influx and lipid synthesis. Conversely, overexpression of MST4 in human hepatocytes exacerbated fat deposition by suppressing mitochondrial fatty acid oxidation and triacylglycerol efflux, while enhancing lipogenesis. In parallel to these reciprocal alterations in lipid storage, we detected substantially decreased or aggravated oxidative/endoplasmic reticulum stress in human hepatocytes with reduced or increased MST4 levels, respectively. Interestingly, MST4 protein was predominantly associated with intracellular lipid droplets in both human and rodent hepatocytes. Conclusion: Together, our results suggest that hepatic lipid droplet-decorating protein MST4 is a critical regulatory node governing susceptibility to NAFLD and warrant future investigations to address the therapeutic potential of MST4 antagonism as a strategy to prevent or mitigate the development and aggravation of this disease.
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28. |
- Casselbrant, Anna, 1970, et al.
(författare)
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Angiotensin II exerts dual actions on sodium-glucose transporter 1-mediated transport in the human jejunal mucosa
- 2015
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 50:9, s. 1068-1075
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. Intestinal glucose absorption is mainly mediated via the sodium-glucose transporter 1 (SGLT1) at the apex of the enterocytes, whereas the glucose transporter 2 (GLUT2) provides a basolateral exit. It has been shown in rats that Angiotensin II (AngII), the principal mediator of renin-angiotensin system (RAS), inhibits jejunal SGLT1-mediated glucose absorption. The aim of the present study was to investigate if a similar mechanism exists also in the human jejunal mucosa. Material and methods. Enteroscopy with mucosal biopsy sampling was performed in 28 healthy volunteers. Functional assessments were performed in Ussing chambers using a pharmacological approach. Western blotting and immunohistochemistry were used to assess the presence of the AngII type 1 (AT1R) and type 2 receptor (AT2R), as well as the glucose transporters SGLT1 and GLUT2. Results. Exposure of the mucosa to 10 mM glucose elicited a »50% increase in the epithelium-generated current (Iep). This glucose-induced electrogenic response was sensitive to the competitive SGLT1 inhibitor phlorizin, but not to AngII when given alone. AngII combined with the AT2R blocker PD123319 markedly inhibited the response. AngII in combination with the AT1R antagonist losartan tended to increase the electrogenic response, whereas direct activation of AT2R using the agonist C21 significantly enhanced the mucosal response to glucose. The AT1R and AT2R as well as SGLT1 and GLUT2 were detected inside the human enterocytes. Conclusions. The pharmacological analysis indicated that activation of AT1R inhibits, whereas activation of AT2R enhances SGLT1-mediated glucose transport in the human jejunal mucosa.
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29. |
- Casselbrant, Anna, 1970, et al.
(författare)
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Morphological Adaptation in the Jejunal Mucosa after Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers: Data from a Randomized Crossover Study
- 2022
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:19
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: The conditions for jejunal glucose absorption in healthy subjects have not been thoroughly studied. In this study we investigated differences in the jejunal villi enlargement factor, as well as ultrastructural aspects of the surface enterocytes and mitochondria, comparing 2 weeks of high-carbohydrate (HCD) versus high-fat diets (HFD). We also measured the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) in relation to jejunal mitochondria. Methods: A single-centre, randomized, unblinded crossover study in 15 healthy volunteers ingesting strictly controlled equicaloric diets (either HCD or HFD), with 60% energy from the respective source. An enteroscopy was carried out after 2 weeks of each diet and jejunal mucosal biopsies were acquired. Conventional histology, immunofluorescent staining, transmission electron microscopy and confocal microscopy were used. Results: The villi did not demonstrate any change in the epithelial enlargement factor. Despite an increased mitosis, there were no changes in apoptotic indices. However, the ultrastructural analysis demonstrated a significant increase in the enlargement factor at the bases of the villi. The mitochondria demonstrated increased amounts of cristae after the HFD. The confocal microscopy revealed increased HMGCS2 per mitochondrial marker at the top of the villi after the HFD compared to the HCD. Conclusion: There is a morphometric adaption in the jejunal mucosa following the 2-week diets, not only on a histological level, but rather on the ultrastructural level. This study supports the notion that mitochondrial HMGCS2 is regulated by the fat content of the diet and is involved in the expression of monosaccharide transporters.
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30. |
- Cederborg, Anna, 1976, et al.
(författare)
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Renal function after liver transplantation: Real-world experience with basiliximab induction and delayed reduced-dose tacrolimus
- 2022
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Ingår i: Digestive and Liver Disease. - : Elsevier BV. - 1590-8658. ; 54:8, s. 1076-1083
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Tidskriftsartikel (refereegranskat)abstract
- Background: Routine use of delayed reduced-dose calcineurin-inhibitor treatment with induction immunosuppression in liver transplantation to minimize post-operative kidney injury is still scarce. Aim: To evaluate real-world experience of basiliximab induction with delayed reduced-dose tacrolimus. Methods: In a retrospective cohort study, kidney function was evaluated pre- and postoperatively by measured glomerular filtration rate (mGFR). Adult patients undergoing liver transplantation between 2000 and 2017 were divided into a conventional treatment group (immediate-introduction of tacrolimus, target trough levels 10–15 ng/mL, and corticosteroids, n = 203) and a revised treatment group (basiliximab induction, reduced-dose tacrolimus, target through levels 5–8 ng/mL, delayed until day three, and mycophenolate mofetil 2000 mg/day, n = 343). Results: Mean mGFR was similar between groups at wait-listing (85.3 vs 84.1 ml/min/1.73m², p = 0.60), but higher in the revised treatment group at 3 (56.8 vs 63.4 ml/min/1.73m², p = 0.004) and 12 months post-transplant (60.9 vs 69.7 ml/min/1.73m², p<0.001); this difference remained after correcting for multiple confounders and was independent of pre-transplant mGFR. In the revised treatment group, biopsy proven acute rejection rate was lower (38% vs. 21%, p<0.001), and graft-survival better (p = 0.01). Conclusion: Basiliximab induction with delayed reduced-dose tacrolimus is associated with less kidney injury when compared to standard-dose tacrolimus, without increased risk of rejection, graft loss or death. © 2021
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31. |
- Clifford, B. L., et al.
(författare)
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FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption
- 2021
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 33:8
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Tidskriftsartikel (refereegranskat)abstract
- FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono-and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids.
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32. |
- Danielsson Borssén, Åsa, et al.
(författare)
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Epidemiology and causes of death in a Swedish cohort of patients with autoimmune hepatitis
- 2017
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 52:9, s. 1022-1028
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidemiological studies of autoimmune hepatitis (AIH) show varying figures on prevalence and incidence, and data on the long-term prognosis are scarce.Objective To investigate the epidemiology, long-term prognosis and causes of death in a Swedish AIH cohort.Material and methods: Data collected from 634 AIH patients were matched to the Cause of Death Registry, and survival analyses were made. Prevalence and incidence were calculated for university hospitals with full coverage of cases and compared to the County of Vasterbotten in Northern Sweden.Results: AIH point prevalence was 17.3/100,000 inhabitants in 2009, and the yearly incidence 1990-2009 was 1.2/100,000 inhabitants and year. The time between diagnosis and end of follow-up, liver transplantation or death was in median 11.3 years (range 0-51.5 years). Men were diagnosed earlier (p<.001) and died younger than women (p=.002). No gender differences were found concerning transplant-free, overall survival and liver-related death. Cirrhosis at diagnosis was linked to an inferior survival (p<.001). Liver-related death was the most common cause of death (32.7%). The relative survival started to diverge from the general population 4 years after diagnosis but a distinct decline was not observed until after more than 10 years.Conclusions: Long-term survival was reduced in patients with AIH. No gender difference regarding prognosis was seen but men died younger, probably as a result of earlier onset of disease. Cirrhosis at diagnosis was a risk factor for poor prognosis and the overall risk of liver-related death was increased.
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33. |
- Dixon, P. H., et al.
(författare)
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GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility. Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.
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34. |
- Efe, C., et al.
(författare)
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Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis
- 2017
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Predniso(lo) ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo) ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.
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35. |
- Efe, C., et al.
(författare)
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Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome
- 2021
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Ingår i: Journal of Gastroenterology and Hepatology. - : Wiley. - 0815-9319 .- 1440-1746. ; 36:4, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aim The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5%vs86.1%,P < 0.001) and seropositive for anti-mitochondrial antibodies (88%vs84%,P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8%vs43.6%,P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76vs1.98 x upper limit of normal [ULN],P = 0.006), aspartate aminotransferase (1.29vs1.50 x ULN,P < 0.001), and total bilirubin (0.53vs0.58 x ULN,P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3%vs16.1%,P = 0.07) and Paris II response (71.4%vs69.4%,P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8%vs90.7%,P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjogren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome. Conclusions Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome.
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36. |
- Efe, C., et al.
(författare)
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Validation of Risk Scoring Systems in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis
- 2019
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Ingår i: American Journal of Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 0002-9270 .- 1572-0241. ; 114:7, s. 1101-1108
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.
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37. |
- Ekerfors, Ulrika, et al.
(författare)
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Muscle performance and fatigue in compensated chronic liver disease.
- 2019
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Ingår i: Scandinavian journal of gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 54:7, s. 925-933
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Tidskriftsartikel (refereegranskat)abstract
- Background: A common and debilitating symptom in patients with chronic liver disease is fatigue (CLD). Muscle dysfunction has been suggested to be a key mechanism of fatigue in CLD. Objective: We aimed to evaluate fatigue and the potential association with muscle performance and physical activity in outpatients with CLD. Methods: Two-hundred seventy outpatients with CLD were included, (52±15years, mean±SD; 151 females) with autoimmune hepatitis (n=49), primary biliary cholangitis (n=45), primary sclerosing cholangitis (n=46), chronic hepatitis B (n=57) or C (n=73). Patients with a Child-Pugh >6 were excluded. The questionnaire Fatigue Impact Scale (FIS) was used to evaluate fatigue, and physical activity was evaluated through a self-reported level of physical activity. Muscle function was assessed with four muscle tests, walking speed, handgrip strength, standing heel-rise test (SHT) and 'Timed Up and Go' test (TUG). Results: The median total FIS score was 30 (40% had FIS > 40, considered high-fatigue). Diminished muscle performance was observed in the SHT (% of predicted value: 53±26%) and with maximum grip strength (85±20%). The FIS score was significantly different between groups of CLDs (p=.004). In multivariate analysis the TUG (p=.001), SHT (p=.005), antidepressants (p<.001), and level of physical activity (p=.001) were associated with fatigue (R2=29%). Subjects with higher levels of physical activity had lower FIS (p<.001). Conclusions: In patients with CLD, fatigue was associated with low muscle performance and reduced level of physical activity, which could be a potential therapeutic target.
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38. |
- Ekerfors, Ulrika, et al.
(författare)
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The influence of muscle performance and fatigue on prognosis in patients with compensated liver disease
- 2023
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Ingår i: BMC Gastroenterology. - 1471-230X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Poor muscle function is associated with a negative prognosis in advanced liver disease but the impact in compensated chronic liver disease is unknown. Similar prognostic uncertainty applies to fatigue. We aimed to assess the prognostic value of muscle performance and fatigue in a cohort of patients with compensated chronic liver disease. Methods We followed 241 patients with compensated chronic liver disease included in a study between 2010 and 2014. Subjects were 52 +/- 15 years (mean +/- SD; 134 females). All subjects performed four muscle function tests: "Timed Up and Go" test, walking speed, handgrip strength, and standing heel-rises. Fatigue was evaluated by fatigue impact scale. Follow up data was acquired through hospital records and registries. Results During follow up of 6.75 +/- 1.4 years, 13 patients died (5.5%) and 11 (4.5%) patients underwent liver transplantation. A timed up and go over 10 s was not significantly associated with a lower survival (Kaplan-Meier, log rank test p = 0.132), or with transplant free survival (p = 0.543), Fig. 3. It was also not specifically associated with liver related causes of death (p = 0.597). The other physical functioning tests and fatigue were not significantly associated with mortality or transplant-free survival (p > 0.05 for all) except for maximal walking speed (2.2 vs. 1.9 m/s, p = 0.007). Conclusions Our study suggests that muscle function and fatigue are not key prognostic factors in compensated chronic liver disease. However, further confirmation in future studies is needed.
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39. |
- Elebring, Erik, 1990, et al.
(författare)
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A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism-Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers
- 2022
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved. Methods: Fifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures. Results: HFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression. Conclusion: Jejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853).
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40. |
- Fan, H. M., et al.
(författare)
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Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 71:4, s. 837-852
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Tidskriftsartikel (refereegranskat)abstract
- Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography-tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11-13 weeks pregnant women with BMI <= 25 or BMI >= 35 kg/m(2) with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI >= 35 kg/m(2) (P < 0.05). In islets, 50 mu mol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.
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41. |
- Fickert, P., et al.
(författare)
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norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis
- 2017
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Ingår i: J Hepatol. - 0168-8278. ; 67:3, s. 549-558
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aim: Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C-23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. Methods: One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. Results: norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500 mg/d groups (p = 0.029, tively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary end-points, such as ALT, AST, gamma-GT, or the rate of patients achieving ALP levels < 1.5 x ULN. Serious adverse events occurred in seven patients in the 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. Conclusions: norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V.
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42. |
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43. |
- Friedrich, D., et al.
(författare)
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Response of fibroblast growth factor 19 and bile acid synthesis after a body weight-adjusted oral fat tolerance test in overweight and obese NAFLD patients: a non-randomized controlled pilot trial
- 2018
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Ingår i: Bmc Gastroenterology. - : Springer Science and Business Media LLC. - 1471-230X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Non-alcoholic fatty liver disease (NAFLD) is common both in obese and overweight patients. Fibroblast growth factor 19 (FGF19), an intestinal hormone, could play a role in the complex pathogenesis of NAFLD. The aim of our study was to investigate responses of FGF19 and bile acid (BA) synthesis after a body weight-adjusted oral fat tolerance test (OFTT) in overweight and obese NAFLD patients. Methods: For this study, we recruited 26 NAFLD patients; 14 overweight (median BMI 28.3 kg/m(2)), 12 obese (35.3 kg/m(2)) and 16 healthy controls (24.2 kg/m(2)). All individuals received 1 g fat (Calogen (R)) per kg body weight orally. Serum concentrations of FGF19 were determined by ELISA. Concentrations of BAs and BA synthesis marker 7 alpha-hydroxy-4-cholesten-3-one (C4) were measured by gas chromatography-mass spectrometry and high-performance liquid chromatography, respectively; all at 0 (baseline), 2, 4 and 6 h during the OFTT. Results: BMI correlated negatively with fasting FGF19 concentrations (rho = - 0.439, p = 0.004). FGF19 levels of obese NAFLD patients were significantly (p = 0.01) lower in the fasting state (median 116.0 vs. 178.5 pg/ml), whereas overweight NAFLD patients had significantly (p = 0.004) lower FGF19 concentrations 2 h after the fat load (median 163.0 vs. 244.5 pg/ml), and lowest values at all postprandial time points as compared to controls. Baseline BA concentrations correlated positively with FGF19 values (rho = 0.306, p = 0.048). In all groups, we observed BA increases during the OFTT with a peak at 2 h but no change in C4 levels in overweight/obese NAFLD patients. Conclusions: Reduced basal gastrointestinal FGF19 secretion and decreased postprandial response to oral fat together with blunted effect on BA synthesis indicate alterations in intestinal or hepatic FXR signaling in overweight and obese NAFLD subjects. The precise mechanism of FGF19 signaling after oral fat load needs further evaluation.
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44. |
- Friis-Liby, Ingalill, et al.
(författare)
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Ikterus och kolestas
- 2012
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Ingår i: Läkartidningen. - 0023-7205. ; 109:46, s. 2093-6
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Tidskriftsartikel (refereegranskat)
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45. |
- Fuchs, C. D., et al.
(författare)
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Absence of Bsep/Abcb11 attenuates MCD diet-induced hepatic steatosis but aggravates inflammation in mice
- 2020
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Ingår i: Liver International. - : Wiley. - 1478-3223 .- 1478-3231. ; 40:6, s. 1366-1377
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Tidskriftsartikel (refereegranskat)abstract
- Background Bile acids (BAs) regulate hepatic lipid metabolism and inflammation. Bile salt export pump (BSEP) KO mice are metabolically preconditioned with a hydrophilic BA composition protecting them from cholestasis. We hypothesize that changes in hepatic BA profile and subsequent changes in BA signalling may critically determine the susceptibility to steatohepatitis. Methods Wild-type (WT) and BSEP KO mice were challenged with methionine choline-deficient (MCD) diet to induce steatohepatitis. Serum biochemistry, lipid profiling as well as intestinal lipid absorption were assessed. Markers of inflammation, fibrosis, lipid and BA metabolism were analysed. Hepatic and faecal BA profile as well as serum levels of the BA synthesis intermediate 7-hydroxy-4-cholesten-3-one (C4) were also investigated. Results Bile salt export pump KO MCD-fed mice developed less steatosis but more inflammation than WT mice. Intestinal neutral lipid levels were reduced in BSEP KO mice at baseline and under MCD conditions. Faecal non-esterified fatty acid concentrations at baseline and under MCD diet were markedly elevated in BSEP KO compared to WT mice. Serum liver enzymes and hepatic expression of inflammatory markers were increased in MCD-fed BSEP KO animals. PPAR alpha protein levels were reduced in BSEP KO mice. Accordingly, PPAR alpha downstream targets Fabp1 and Fatp5 were repressed, while NF kappa B subunits were increased in MCD-fed BSEP KO mice. Farnesoid X receptor (FXR) protein levels were reduced in MCD-fed BSEP KO vs WT mice. Hepatic BA profile revealed elevated levels of T beta MCA, exerting FXR antagonistic action, while concentrations of TCA (FXR agonistic function) were reduced. Conclusion Presence of hydroxylated BAs result in increased faecal FA excretion and reduced hepatic lipid accumulation. This aggravates development of MCD diet-induced hepatitis potentially by decreasing FXR and PPAR alpha signalling.
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46. |
- Fuchs, Claudia Daniela, et al.
(författare)
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Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2-/- mice by modulating composition, signalling and excretion of faecal bile acids.
- 2018
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:9, s. 1683-1691
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Tidskriftsartikel (refereegranskat)abstract
- Interruption of the enterohepatic circulation of bile acids (BAs) may protect against BA-mediated cholestatic liver and bile duct injury. BA sequestrants are established to treat cholestatic pruritus, but their impact on the underlying cholestasis is still unclear. We aimed to explore the therapeutic effects and mechanisms of the BA sequestrant colesevelam in a mouse model of sclerosing cholangitis.Mdr2-/- mice received colesevelam for 8 weeks. Gene expression profiles of BA homeostasis, inflammation and fibrosis were explored in liver, intestine and colon. Hepatic and faecal BA profiles and gut microbiome were analysed. Glucagon-like peptide 1 (GLP-1) levels in portal blood were measured by ELISA. Furthermore, Mdr2-/- mice as well as wild-type 3,5-diethoxy-carbonyl-1,4-dihydrocollidine-fed mice were treated with GLP-1-receptor agonist exendin-4 for 2 weeks prior to analysis.Colesevelam reduced serum liver enzymes, BAs and expression of proinflammatory and profibrogenic markers. Faecal BA profiling revealed increased levels of secondary BAs after resin treatment, while hepatic and biliary BA composition showed a shift towards more hydrophilic BAs. Colonic GLP-1 secretion, portal venous GLP-1 levels and intestinal messenger RNA expression of gut hormone Proglucagon were increased, while ileal Fgf15 expression was abolished by colesevelam. Exendin-4 treatment increased bile duct mass without promoting a reactive cholangiocyte phenotype in mouse models of sclerosing cholangitis. Microbiota analysis showed an increase of the phylum δ-Proteobacteria after colesevelam treatment and a shift within the phyla Firmicutes from Clostridiales to Lactobacillus.Colesevelam increases faecal BA excretion and enhances BA conversion towards secondary BAs, thereby stimulating secretion of GLP-1 from enteroendocrine L-cells and attenuates liver and bile duct injury in Mdr2-/- mice.
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47. |
- Fuchs, C. D., et al.
(författare)
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GLP-2 Improves Hepatic Inflammation and Fibrosis in Mdr2-/- Mice Via Activation of NR4a1/Nur77 in Hepatic Stellate Cells and Intestinal FXR Signaling
- 2023
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Ingår i: Cellular and Molecular Gastroenterology and Hepatology. - 2352-345X. ; 16:5, s. 847-856
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Glucagon-like peptide (GLP)-2 may exert antifibrotic effects on hepatic stellate cells (HSCs). Thus, we aimed to test whether application of the GLP-2 analogue teduglutide has hepatoprotective and antifibrotic effects in the Mdr2/Abcb4(-/-) mouse model of sclerosing cholangitis displaying hepatic inflammation and fibrosis. METHODS: Mdr2(-/-) mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry. Activated HSCs (LX2 cells) and immortalized human hepatocytes and human intestinal organoids were treated with GLP-2. mRNA profiling by reverse transcription polymerase chain reaction and elec-trophoretic mobility shift assay using cytosolic and nuclear protein extracts was performed. RESULTS: Hepatic inflammation, fibrosis, and reactive chol-angiocyte phenotype were improved in GLP-2-treated Mdr2(-/-) mice. Primary HSCs isolated from Mdr2(-/-)mice and LX2 cells exposed to GLP-2 in vitro displayed significantly increased mRNA expression levels of NR4a1/Nur77 (P < .05). Electro-phoretic mobility shift assay revealed an increased nuclear NR4a1 binding after GLP-2 treatment in LX2 cells. Moreover, GLP-2 alleviated the Tgf beta-mediated reduction of NR4a1 nuclear binding activity. In vivo, GLP-2 treatment of Mdr2(-/-) mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR. Serum Fgf15 levels were increased in Mdr2(-/-) mice treated with GLP-2. Accordingly, GLP-2 treatment of human intestinal organoids activated their FXR-FGF19 signaling axis. CONCLUSIONS: GLP-2 treatment increased NR4a1/Nur77 activation in HSCs, subsequently attenuating their activation. GLP-2 promoted intestinal Fxr-Fgf15/19 signaling resulting in reduced Cyp7a1 and increased Cyp2c70 expression in the liver, contributing to hepatoprotective and antifibrotic effects of GLP2 in the Mdr2(-/-) mouse model.
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48. |
- Fuchs, Claudia D, et al.
(författare)
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Metabolic preconditioning protects BSEP/ABCB11(-/-) mice against cholestatic liver injury.
- 2017
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 66:1, s. 95-101
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Tidskriftsartikel (refereegranskat)abstract
- Cholestasis is characterized by intrahepatic accumulation of potentially cytotoxic bile acids (BAs) subsequently leading to liver injury with disruption of hepatocellular integrity, inflammation, fibrosis and ultimately liver cirrhosis. Bile salt export pump (BSEP/ABCB11) is the main canalicular BA transporter and therefore the rate limiting step for hepatobiliary BA excretion. In this study we aimed to investigate the role of BSEP/ABCB11 in the development of acquired cholestatic liver and bile duct injury.Wild-type (WT) and BSEP knockout (BSEP(-/-)) mice were subjected to common bile duct ligation (CBDL) or 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) feeding as models for cholestasis with biliary obstruction and bile duct injury. mRNA expression profile, serum biochemistry, liver histology, immunohistochemistry, hepatic hydroxyproline levels and BA composition as well as biliary pressure were assessed.BSEP(-/-) mice were protected against acquired cholestatic liver injury induced by 7days of CBDL or 4weeks of DDC feeding, as reflected by unchanged serum levels of liver transaminases, alkaline phosphatase and BAs. Notably, BSEP(-/-) mice were also protected from cholestasis-induced hepatic inflammation and biliary fibrosis. In line with induced BA detoxification/hydroxylation pathways in BSEP(-/-) mice, polyhydroxylated BAs were increased 4-fold after CBDL and 6-fold after DDC feeding in comparison with cholestatic WT mice. Finally, following CBDL, biliary pressure in WT mice increased up to 47mmH2O but remained below 11mmH2O in BSEP(-/-) mice.Metabolic preconditioning with subsequent changes in BA metabolism favors detoxification of potentially toxic BAs and thereby protects BSEP(-/-) mice from cholestatic liver and bile duct injury.Reduced hepatobiliary bile acid transport due to loss of BSEP function leads to increased hydroxylation of bile acids in the liver. Metabolic preconditioning with a hydrophilic bile pool protects the BSEP(-/-) mice from acquired cholestatic liver disease.
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49. |
- Fuchs, C. D., et al.
(författare)
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Tetrahydroxylated bile acids improve cholestatic liver and bile duct injury in the Mdr2(-/-) mouse model of sclerosing cholangitis via immunomodulatory effects
- 2022
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Ingår i: Hepatology communications.. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 6:9, s. 2368-2378
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Tidskriftsartikel (refereegranskat)abstract
- Bile salt export pump (Bsep) (Abcb11)(-/-) mice are protected from acquired cholestatic injury due to metabolic preconditioning with a hydrophilic bile acid (BA) pool with formation of tetrahydroxylated bile acids (THBAs). We aimed to explore whether loss of Bsep and subsequent elevation of THBA levels may have immunomodulatory effects, thus improving liver injury in the multidrug resistance protein 2 (Mdr2) (Abcb4)(-/-) mouse. Cholestatic liver injury in Mdr2(-/-)Bsep(-/-) double knockout (DKO), Mdr2(-/-), Bsep(-/-), and wild-type mice was studied for comparison. Mdr2(-/-) mice were treated with a THBA (3 alpha,6 alpha,7 alpha,12 alpha-Tetrahydroxycholanoic acid). RNA/protein expression of inflammatory/fibrotic markers were investigated. Serum BA-profiling was assessed by ultra-performance liquid chromatography tandem mass spectrometry. Hepatic immune cell profile was quantified by flow cytometric analysis (FACS). In vitro, the THBA effect on chenodeoxycholic acid (CDCA)-induced inflammatory signaling in hepatocyte and cholangiocytes as well as lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-induced macrophage activation was analyzed. In contrast to Mdr2(-/-), DKO mice showed no features of sclerosing cholangitis. Sixty-seven percent of serum BAs in DKO mice were polyhydroxylated (mostly THBAs), whereas Mdr2(-/-) mice did not have these BAs. Compared with Mdr2(-/-), DKO animals were protected from hepatic inflammation/fibrosis. THBA feeding in Mdr2(-/-) mice improved liver injury. FACS analysis in DKO and Mdr2(-/-) THBA-fed mice showed changes of the hepatic immune cell profile towards an anti-inflammatory pattern. Early growth response 1 (EGR1) protein expression was reduced in DKO and in Mdr2(-/-) THBA-fed mice compared with Mdr2(-/-) control mice. In vitro, THBA-reduced CDCA induced EGR1 protein and mRNA expression of inflammatory markers in hepatocytes and cholangiocytes. LPS/IFN-gamma-induced macrophage activation was ameliorated by THBA. THBAs repress EGR1-related key pro-inflammatory pathways. Conclusion: THBA and their downstream targets may represent a potential treatment strategy for cholestatic liver diseases.
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50. |
- Geenes, V., et al.
(författare)
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Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy
- 2015
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Ingår i: European Journal of Obstetrics & Gynecology and Reproductive Biology. - : Elsevier BV. - 0301-2115 .- 1872-7654. ; 189, s. 59-63
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe the use of combined ursodeoxycholic acid (UDCA) and rifampicin treatment in intrahepatic cholestasis of pregnancy (ICP). Study design: A questionnaire survey of 27 women with 28 affected pregnancies identified via the UK and International Obstetric Medicine forum. The clinical case notes of women with ICP treated with combined UDCA and rifampicin therapy were reviewed, and data regarding maternal and perinatal outcomes extracted. Results: Serum bile acids remained high whilst taking UDCA as monotherapy. In 14 pregnancies (54%) serum bile acids decreased following the introduction of rifampicin. In 10 pregnancies (38%), there was a 50% reduction in serum bile acids. There were no adverse effects reported with either drug. Conclusions: This is the first report of the use of rifampicin in ICP. The data suggest that combined treatment with UDCA and rifampicin is an effective way of treating women with severe ICP who do not respond to treatment with UDCA alone. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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