| 1. |
- Amrutkar, Manoj, et al.
(författare)
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Protein kinase STK25 regulates hepatic lipid partitioning and progression of liver steatosis and NASH
- 2015
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Ingår i: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:4, s. 1564-1576
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease, and 10% to 20% of NAFLD patients progress to nonalcoholic steatohepatitis (NASH). The molecular pathways controlling progression to NAFLD/NASH remain poorly understood. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of whole-body insulin and glucose homeostasis. This study investigates the role of STK25 in liver lipid accumulation and NASH. Stk25 transgenic mice challenged with a high-fat diet displayed a dramatic increase in liver steatosis and hepatic insulin resistance compared to wild-type siblings. Focal fibrosis, hepatocellular damage, and inflammation were readily seen in transgenic but not wild-type livers. Transgenic livers displayed reduced beta-oxidation and triacylglycerol secretion, while lipid uptake and synthesis remained unchanged. STK25 was associated with lipid droplets, colocalizing with the main hepatic lipid droplet-coating protein adipose differentiation-related protein, the level of which was increased 3.8 +/- 0.7-fold in transgenic livers (P < 0.01), while a key hepatic lipase, adipose triacylglycerol lipase, was translocated from the lipid droplets surface to the cytoplasm, providing the likely mechanism underlying the effect of STK25. In summary, STK25 is a lipid droplet-associated protein that promotes NAFLD through control of lipid release from the droplets for beta-oxidation and triacylglycerol secretion. STK25 also drives pathogenesis of NASH.
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| 2. |
- Burza, Maria Antonella, 1980, et al.
(författare)
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DEPDC5 variants increase fibrosis progression in Europeans with chronic HCV infection.
- 2016
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Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 63:2, s. 418-427
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Tidskriftsartikel (refereegranskat)abstract
- Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in Europeans with chronic HCV infection. In a Northern Italian discovery cohort (n=477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n=150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n=300; p=0.049). The association of rs1012068 with moderate-severe fibrosis was confirmed in an independent cross-sectional German cohort (n=415; p=0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n=247; p=0.027). Next, we examined the distribution of non-synonymous DEPDC5 variants in the overall cross-sectional cohort (n=912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (p=0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX-2). In these cells, down-regulation of DEPDC5 resulted in increased expression of β-catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression.
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| 3. |
- Caddeo, Andrea, et al.
(författare)
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Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia.
- 2018
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Ingår i: Nutrition, metabolism, and cardiovascular diseases : NMCD. - : Elsevier BV. - 1590-3729 .- 0939-4753. ; 28, s. 158-164
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Tidskriftsartikel (refereegranskat)abstract
- Type I hyperlipoproteinemia, also known as familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disorder caused by variants in LPL, APOC2, APOA5, LMF1 or GPIHBP1 genes. The aim of this study was to identify novel variants in the LPL gene causing lipoprotein lipase deficiency and to understand the molecular mechanisms.A total of 3 individuals with severe hypertriglyceridemia and recurrent pancreatitis were selected from the Lipid Clinic at Sahlgrenska University Hospital and LPL was sequenced. Invitro experiments were performed in human embryonic kidney 293T/17 (HEK293T/17) cells transiently transfected with wild type or mutant LPL plasmids. Cell lysates and media were used to analyze LPL synthesis and secretion. Media were used to measure LPL activity. Patient 1 was compound heterozygous for three known variants: c.337T>C (W113R), c.644G>A (G215E) and c.1211T>G (M404R); patient 2 was heterozygous for the known variant c.658A>C (S220R) while patient 3 was homozygous for a novel variant in the exon 5 c.679G>T (V227F). All the LPL variants identified were loss-of-function variants and resulted in a substantial reduction in the secretion of LPL protein.We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic.
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| 4. |
- Fagman, Johan Bourghardt, 1980, et al.
(författare)
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The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
- 2015
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860 .- 0892-6638. ; 29:4, s. 1540-1550
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Tidskriftsartikel (refereegranskat)abstract
- Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.-Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J. -O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
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| 5. |
- Pavanello, Chiara, et al.
(författare)
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Individuals with familial hypercholesterolemia and cardiovascular events have higher circulating Lp(a) levels.
- 2019
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Ingår i: Journal of clinical lipidology. - : Elsevier BV. - 1933-2874. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular disease (CVD) is a major cause of mortality and morbidity. Increased low-density lipoprotein cholesterol (LDL-C) level is its major risk factor. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated LDL-C since birth and subsequent premature CVD. There is a heterogeneity in the CVD onset in patients with FH. This is potentially due to the presence of other independent risk factors. Lipoprotein(a) [Lp(a)] is an LDL-like particle and represents a strong risk factor for CVD.Our objective was to understand the contribution of Lp(a) in the susceptibility to CVD in individuals with genetic diagnosis of FH.We measured Lp(a) levels in 2 independent and well-characterized genetic-FH cohorts: the FH-Gothenburg cohort (n=190) and the FH-CEGP Milan cohort (n=160). The genetic diagnosis was performed by targeted next-generation sequencing (FH-Gothenburg and part of the FH-CEGP Milan cohort), or by Sanger sequencing.We show that among individuals with genetic diagnosis of FH, those with previous CVD had higher Lp(a) levels. In addition, analyzing the response to the lipid-lowering therapies, we have also shown that statins had the same LDL-C-lowering effect irrespective of the type of FH-causative mutation. However, when we examined the lipid-lowering effect of proprotein convertase subtilisin/kexin type 9 inhibition by antibodies, we observed a trend in a better reduction of the LDL-C level in carriers of nonsense mutations.In conclusion, our results suggest that Lp(a) contributes to CVD onset in individuals with genetic diagnosis of FH. Our finding supports the importance to identify an efficacious therapy to lower Lp(a) in patients with FH to prevent CVD onset or recurrence.
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| 6. |
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| 7. |
- Pirazzi, Carlo, et al.
(författare)
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High prevalence of genetic determined familial hypercholesterolemia in premature coronary artery disease.
- 2019
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Ingår i: The application of clinical genetics. - 1178-704X. ; 12, s. 71-78
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Tidskriftsartikel (refereegranskat)abstract
- Background: Premature coronary artery disease (CAD) is a major cause of mortality and morbidity. Increased low-density lipoprotein-cholesterol (LDL-C) level is a major risk factor for CAD and thus the main target for its prevention. Familial Hypercholesterolemia (FH) is a genetic inherited disorder characterized by high LDL-C, and subsequent premature CAD development. Early drug treatment with lipid-lowering medications in FH prevents cardiovascular disease onset. The FH prevalence in the Northern European general population is 0.3%, and it is estimated that it explains 20% of premature CAD cases in individuals with familial clustering. Despite the wide number of papers showing the prevalence of clinical FH in cardiovascular disease, the prevalence of genetic FH in individuals with premature CAD is not yet well known. Here, we examined the prevalence of genetically determined FH in individuals with premature CAD. Patients and methods: 66 patients who underwent coronary angiography with suspected premature acute coronary syndrome (age <50 years for men and <55 years for women) underwent genetic screening to identify FH-causing mutations. All patients underwent physical and clinical examinations. Information about family and personal history, drug therapy and habits were also collected. Results: We found FH-causative mutations in 3/66 (4.5%) screened individuals with premature CAD. When considering individuals with confirmed CAD after coronary angiography, the FH mutation prevalence was 6.1% (3/49). After excluding individuals with classical risk factors for CAD other than hypercholesterolemia, the FH mutation prevalence raised to 15.8% (3/19). Conclusion: In conclusion, we found that individuals with premature CAD have a more than 15-fold increased prevalence of FH mutations compared to the general population.
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| 8. |
- Pirazzi, Carlo, et al.
(författare)
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PCSK9 Inhibitors in a Statin-Intolerant Transgender Man With Heterozygous Familial Hypercholesterolemia: A Case Report
- 2019
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 3:8, s. 1461-1464
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Tidskriftsartikel (refereegranskat)abstract
- In female-to-male transgender individuals, testosterone is used to induce masculinization. Sex steroid therapy may increase circulating triglyceride and low-density lipoprotein cholesterol (LDL-C) levels and may decrease high-density lipoprotein cholesterol (HDL-C) levels, resulting in a more atherogenic lipid profile. These potentially adverse effects of androgen therapy may be exacerbated by the presence of familial hypercholesterolemia (FH). We describe the case of a transgender man with genetically diagnosed FH who was intolerant to statins and was started on a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to control his lipoproteins more effectively. The 35-year-old female-to-male transgender individual was referred to our center with a history of elevated LDL-C levels. Despite treatment with high doses of high-potency statins and ezetimibe, he had never achieved a sustained reduction in LDL-C; his levels of LDL-C were fluctuating between 170 and 344 mg/dL (4.4 and 8.9 mmol/L). Moreover, he developed side effects to statins in the form of myalgia and discontinued statin treatment. At the Sahlgrenska Lipid Clinic, a genetic diagnosis of heterozygous FH was established, and PCSK9 inhibitor therapy was started. The patient's LDL-C level has been reduced by approximately 40% for 23 months, and no adverse events have been reported.
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