Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.

Staels, Bart; Vu‐Dac, Ngoc; Kosykh, V. P.; Saladin, Régis; Fruchart, Jean‐Charles; Dallongeville, Jean; Auwerx, Johan

doi:10.1172/jci117717

Cited by 397 publications

(270 citation statements)

References 56 publications

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“…Studies in animals indicate that PPAR-α agonists increase hepatic fat oxidation and reduce hepatic fat content in association with enhanced insulin-mediated suppression of EGP [3,7,43,48]. Although hepatic fat oxidation was not measured in the present study, we did not observe a significant reduction in hepatic fat content or an increase in hepatic insulin sensitivity (in contrast to PIO therapy) following FENO therapy.…”

Section: Discussioncontrasting

confidence: 81%

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferatoractivated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n=8) or PIO (n=7) for 3 months, followed by the addition of the other agent for 3 months in an openlabel study. Subjects received a 4 h hyperinsulinaemiceuglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PIO, fasting plasma glucose (FPG) (p<0.05) and HbA 1c (p<0.01) decreased, while plasma adiponectin (AD) (5.5±0.9 to 13.8±3.5 μg/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (R d ) (23.8 ± 3.8 to 40.5 ± 4.4 μmol kg −1 min −1 , p < 0.005) increased. After FENO, FPG, HbA 1c , AD and R d did not change. PIO reduced fasting NEFA (784±53 to 546± 43 μmol/l, p<0.05), triacylglycerol (2.12±0.28 to 1.61± 0.22 mmol/l, p<0.05) and hepatic fat content (20.4±4.8 to 10.2±2.5%, p<0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20± 0.14 to 1.59± 0.13 mmol/l, p<0.01).Addition of FENO to PIO had no effect on R d , FPG, HbA 1c , NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61±0.22 to 1.00±0.15 mmol/l, p<0.05). Addition of PIO to FENO increased R d (24.9±4.4 to 36.1± 2.2 μmol kg −1 min −1 , p<0.005) and AD (4.1±0.8 to 13.1± 2.5 μg/ml, p<0.005) and reduced FPG (p<0.05), HbA 1c (p<0.05), NEFA (p<0.01), hepatic fat content (18.3±3.1 to 13.5±2.1%, p<0.03) and triacylglycerol (1.59±0.13 to 0.96±0.9 mmol/l, p<0.01). Muscle adenosine 5′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2±0.2 to 2.2±0.3, p<0.01). Conclusions/interpretation We conclude that PPAR-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

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Section: Discussioncontrasting

confidence: 81%

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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“…A positive feedback loop through PPAR␣ is suggested by LPL͞VLDL-mediated induction of LPL expression itself. The functional impact of this pathway may be augmented by PPAR␣-mediated repression of the endogenous LPL inhibitor ApoCIII (37). By examining the relationship of this lipolytic pathway to nuclear receptor activation, new insights are gained into both LPL and PPAR function.…”

Section: Discussionmentioning

confidence: 99%

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase

Ziouzenkova

Perrey

Asatryan

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

218

176

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“…Caco-2 cells (passages [35][36][37][38][39][40][41][42][43][44][45], used for transfection experiments, were cultured in a controlled environment (37°C, 5% CO 2 ) in Dulbecco's modified Eagle's medium, 4 mM glutamine, 1% non-essential amino acids, 100 units/ml penicillin, 100 g/ml streptomycin supplemented with 20% FCS. Medium was changed every 2 days.…”

Section: Methodsmentioning

confidence: 99%

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Landrier

Thomas

Grober

et al. 2004

Journal of Biological Chemistry

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Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5 -deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position ؊67/؊55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPAR␣ agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPAR␣-null animals demonstrating the direct implication of PPAR␣ in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPAR␣ mRNA levels both in vitro and in vivo and activated the mouse PPAR␣ promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPAR␣. Moreover, PPAR␣ might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. The resulting lower intracellular cholesterol concentration after statin treatment leads to a proteolytic activation of the transcription factor sterol responsive element-binding protein-2 (SREBP-2), 1 which up-regulates several genes controlling cholesterol homeostasis, including the LDL receptor (LDLr) (1). Induction of LDLr in the liver enhances clearance of circulating LDL resulting in decreased plasma LDL-cholesterol levels. Statins also increase, at least in part via a PPAR␣-dependent mechanism (2), the level of high density lipoproteins (3, 4). As a consequence, statins improve the blood cholesterol profile and markedly reduce cardiovascular mortality and morbidity in dyslipidemic patients (5-7). Statins also influence plasma TG and NEFA levels in rats and humans (4, 8 -11) through mechanisms not yet fully elucidated. Sustained hepatic clearance of TG-rich very low density lipoproteins by the LDLr (12), statin-dependent up-regulation of the lipoprotein lipase (LPL) gene, and down-regulation of the LPL inhibitor apolipoprotein C-III (13) may all contribute to the TG-lowering effect of statins. By contrast, it is not known if statins control th...

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Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates.

Abstract: IntroductionEpidemiological and transgenic animal studies have implicated apo C-IlI as a major determinant of plasma triglyceride metabolism. Since

Cited by 397 publications

References 56 publications

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

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