| 1. |
- Saliba-Gustafsson, P., et al.
(författare)
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Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy
- 2019
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 660-675
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Tidskriftsartikel (refereegranskat)abstract
- Background Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. Results The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. Conclusions For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.
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| 7. |
- 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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- Pedrelli, M., et al.
(författare)
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Athero-protective properties of plasma lipoproteins from brown bears (URSUS ARCTOS) during hibernation and active state
- 2020
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 315, s. E69-E70
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: Plasma cholesterol (TC) and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than in healthy humans. Yet, bears display no signs of atherosclerosis. To explore this apparent paradox, lipoprotein structure and function of brown bears were analyzed and compared with those of healthy humans.Methods: Blood from the same wild free-ranging Swedish brown bears (n=10) was drawn during hibernation (winter) and active state (summer). Plasma lipoproteins were separated by size exclusion chromatography, ultracentrifugation and gel-electrophoresis. LDL binding to arterial proteoglycans (PGs) was measured. Data are presented as median (10th - 90th percentile).Results: During hibernation bear LDL carried 4.6 (2.3-5.9) mmol/L cholesterol esters (CE), 1.5 (1.1-2.4) mmol/L unesterified (UC), 3.7 (2.1-4.9) mmol/L TG and 2.5 (1.8-3.4) mmol/L phospholipid (PL). Human LDL were smaller than bear LDL, which were proportionally richer in TG (winter 31 (26-33)%, summer 30 (22-40)%vs human 9% (7-15); p<0.001) and had less CE (winter 36 (26-45)%, summer 25 (21-37)%vs human 48 (46-55)%; p<0.01)). Bear LDL were less positively charged and showed a pre-ß motility on agarose gel. Thus, bear LDL had about 10 times lower binding to PGs than human LDL.Conclusions: Despite high TC and TG levels, bear lipoproteins were less atherogenic than the human analogues. This was due to low LDL affinity for PGs, secondary to increased TG and PL, and to low positive charge. Our study provides further mechanistic insights for the atherosclerosis development, which is driven by the circulating lipoprotein composition and functions rather than plasma absolute lipid levels.
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- Archer, A, et al.
(författare)
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Fasting-induced FGF21 is repressed by LXR activation via recruitment of an HDAC3 corepressor complex in mice
- 2012
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Ingår i: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 1944-9917 .- 0888-8809. ; 26:12, s. 1980-1990
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Tidskriftsartikel (refereegranskat)abstract
- The liver plays a pivotal role in the physiological adaptation to fasting and a better understanding of the metabolic adaptive responses may give hints on new therapeutic strategies to control the metabolic diseases. The liver X receptors (LXRs) are well-established regulators of lipid and glucose metabolism. More recently fibroblast growth factor 21 (FGF21) has emerged as an important regulator of energy homeostasis. We hypothesized that the LXR transcription factors could influence Fgf21 expression, which is induced in response to fasting. Wild-type, LXRα−/−, and LXRβ−/− mice were treated for 3 d with vehicle or the LXR agonist GW3965 and fasted for 12 h prior to the killing of the animals. Interestingly, serum FGF21 levels were induced after fasting, but this increase was blunted when the mice were treated with GW3965 independently of genotypes. Compared with wild-type mice, GW3965-treated LXRα−/− and LXRβ−/− mice showed improved insulin sensitivity and enhanced ketogenic response at fasting. Of note is that during fasting, GW3965 treatment tended to reduce liver triglycerides as opposed to the effect of the agonist in the fed state. The LXR-dependent repression of Fgf21 seems to be mainly mediated by the recruitment of LXRβ onto the Fgf21 promoter upon GW3965 treatment. This repression by LXRβ occurs through the recruitment and stabilization of the repressor complex composed of retinoid-related orphan receptor-α/Rev-Erbα/histone deacetylase 3 onto the Fgf21 promoter. Our data clearly demonstrate that there is a cross talk between the LXR and FGF21 signaling pathways in the adaptive response to fasting.
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- Korach-Andre, M, et al.
(författare)
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Liver X receptors regulate de novo lipogenesis in a tissue-specific manner in C57BL/6 female mice
- 2011
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 301:1, s. E210-E222
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Tidskriftsartikel (refereegranskat)abstract
- The liver X receptors (LXRs) play a key role in cholesterol and bile acid metabolism but are also important regulators of glucose metabolism. Recently, LXRs have been proposed as a glucose sensor affecting LXR-dependent gene expression. We challenged wild-type (WT) and LXRαβ−/−mice with a normal diet (ND) or a high-carbohydrate diet (HCD). Magnetic resonance imaging showed different fat distribution between WT and LXRαβ−/−mice. Surprisingly, gonadal (GL) adipocyte volume decreased on HCD compared with ND in WT mice, whereas it slightly increased in LXRαβ−/−mice. Interestingly, insulin-stimulated lipogenesis of isolated GL fat cells was reduced on HCD compared with ND in LXRαβ−/−mice, whereas no changes were observed in WT mice. Net de novo lipogenesis (DNL) calculated from V̇o2and V̇co2was significantly higher in LXRαβ−/−than in WT mice on HCD. Histology of HCD-fed livers showed hepatic steatosis in WT mice but not in LXRαβ−/−mice. Glucose tolerance was not different between groups, but insulin sensitivity was decreased by the HCD in WT but not in LXRαβ−/−mice. Finally, gene expression analysis of adipose tissue showed induced expression of genes involved in DNL in LXRαβ−/−mice compared with WT animals as opposed to the liver, where expression of DNL genes was repressed in LXRαβ−/−mice. We thus conclude that absence of LXRs stimulates DNL in adipose tissue, but suppresses DNL in the liver, demonstrating opposite roles of LXR in DNL regulation in these two tissues. These results show tissue-specific regulation of LXR activity, a crucial finding for drug development.
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| 22. |
- Liang, N, et al.
(författare)
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Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1684-
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Tidskriftsartikel (refereegranskat)abstract
- Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.
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| 32. |
- Aloysius, TA, et al.
(författare)
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Plasma Cholesterol- and Body Fat-Lowering Effects of Chicken Protein Hydrolysate and Oil in High-Fat Fed Male Wistar Rats
- 2022
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:24
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Tidskriftsartikel (refereegranskat)abstract
- Rest raw materials provide a new source of bioactive dietary ingredients, and this study aimed to determine the health effects of diets with chicken protein hydrolysate (CPH) and chicken oil (CO) generated from deboned chicken meat. Male Wistar rats (n = 56) were divided into seven groups in three predefined sub-experiments to study the effects of protein source (casein, chicken fillet, pork fillet, and CPH), the dose-effect of CPH (50% and 100% CPH), and the effects of combining CPH and CO. Rats were fed high-fat diets for 12 weeks, and casein and chicken fillet were used as controls in all sub-experiments. While casein, chicken-, or pork fillet diets resulted in similar weight gain and plasma lipid levels, the CPH diet reduced plasma total cholesterol. This effect was dose dependent and accompanied with the reduced hepatic activities of acetyl-CoA carboxylase and fatty acid synthase. Further, rats fed combined CPH and CO showed lower weight gain, and higher hepatic mitochondrial fatty acid oxidation, plasma L-carnitine, short-chain acylcarnitines, TMAO, and acetylcarnitine/palmitoylcarnitine. Thus, in male Wistar rats, CPH and CO lowered plasma cholesterol and increased hepatic fatty acid oxidation compared to whole protein diets, pointing to potential health-beneficial bioactive properties of these processed chicken rest raw materials.
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| 33. |
- 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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| 46. |
- Pedrelli, Matteo, et al.
(författare)
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Vasculoprotective properties of plasma lipoproteins from brown bears (Ursus arctos)
- 2021
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Ingår i: Journal of Lipid Research. - : Elsevier. - 0022-2275 .- 1539-7262. ; 62
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5-10 times lower binding to arterial PGs than human LDL. Finally, plasma CEC was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL for arterial PGs and an elevated CEC of bear plasma.
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| 47. |
- Pigazzani, F, et al.
(författare)
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The Prognostic Value of Derivatives-Reactive Oxygen Metabolites (d-ROMs) for Cardiovascular Disease Events and Mortality: A Review
- 2022
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Ingår i: Antioxidants (Basel, Switzerland). - : MDPI AG. - 2076-3921. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress participates in the development and exacerbation of cardiovascular diseases (CVD). The ability to promptly quantify an imbalance in an individual reductive-oxidative (RedOx) state could improve cardiovascular risk assessment and management. Derivatives-reactive oxygen metabolites (d-ROMs) are an emerging biomarker of oxidative stress quantifiable in minutes through standard biochemical analysers or by a bedside point-of-care test. The current review evaluates available data on the prognostic value of d-ROMs for CVD events and mortality in individuals with known and unknown CVD. Outcome studies involving small and large cohorts were analysed and hazard ratio, risk ratio, odds ratio, and mean differences were used as measures of effect. High d-ROM plasma levels were found to be an independent predictor of CVD events and mortality. Risk begins increasing at d-ROM levels higher than 340 UCARR and rises considerably above 400 UCARR. Conversely, low d-ROM plasma levels are a good negative predictor for CVD events in patients with coronary artery disease and heart failure. Moreover, combining d-ROMs with other relevant biomarkers routinely used in clinical practice might support a more precise cardiovascular risk assessment. We conclude that d-ROMs represent an emerging oxidative-stress-related biomarker with the potential for better risk stratification both in primary and secondary cardiovascular prevention.
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