Fenofibrate prevents orotic acid—Induced hepatic steatosis in rats

Ferreira, Adaliene Versiani Matos; Parreira, Gleydes G.; Porto, Laura Cristina Jardim; Mario, Érica Guihen; Puerto, Helen L. Del; Martins, Almir de Sousa; Botion, Leida Maria

doi:10.1016/j.lfs.2008.02.003

Cited by 20 publications

(14 citation statements)

References 52 publications

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“…A lack of VLDLR signifi cantly blunted the TG-lowering effect of fenofi brate in mice with HFD-induced hyperlipidemia, confi rming that the upregulation of liver VLDLR is essential and necessary for VLDL-TG metabolism. This fi nding is in agreement with the results of a study by Tacken et al ( 20 ), which showed that the overexpression of VLDLR was associated with decreased VLDL-rich TG levels in VLDLR steatosis in rats receiving orotic acid and in mice with spontaneous hepatic steatosis ( 26,27 ). These studies support the theory that fenofi brate-regulated increases in the expression of liver VLDLR might not cause excess TG uptake but will improve TG clearance in the liver.…”

Section: Discussionsupporting

confidence: 92%

Upregulation of hepatic VLDLR via PPARα is required for the triglyceride-lowering effect of fenofibrate

Gao

Shen

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org progression and increased severity of diabetic complications. The dysregulation of hepatic VLDL secretion is believed to be the mechanism underlying increases in TG-related VLDL and is responsible for the pathogenesis of hepatic insulin resistance in type 2 diabetes, representing a principal target for clinical intervention.Fenofi brate, a fi brate-derived drug, was widely used in the treatment of dyslipidemia in diabetic patients for decades prior to the use of statins ( 3, 4 ). Fibrate drugs reduce plasma TG-related VLDLs, raise plasma HDLs ( 5 ), and have a modest effect on LDL cholesterol levels ( 6 ). Fenofi brate acts as a specifi c agonist of PPAR ␣ , a nuclear hormone receptor that functions as a transcription factor and regulates the expression of a number of genes involved in lipid metabolism and insulin resistance. Fenofibrate has been reported to reduce the body weight gain upon high-fat diet (HFD) stimulation ( 7 ). PPAR ␣ lowers serum TG by infl uencing many genes involved in VLDL production, lipid traffi cking, and TG-rich lipoprotein clearance ( 8 ). For example, PPAR ␣ increases the expression of liver microsomal TG transfer protein (MTTP), a protein that mediates the lipidation of apoB100 to form a nascent VLDL ( 9 ); the expression of liver LPL, an enzyme that mediates the clearance of TG-rich VLDL and chylomicrons ( 10 ); and the synthesis of apoC-III ( 11 ), apoA-II ( 12 ), and apoA-V ( 13 ). However, the precise genes underlying the suppressive effect of PPAR ␣ agonists on hepatic VLDL metabolism currently are not well understood.The VLDL receptor (VLDLR), a member of the LDL receptor (LDLR) family, is widely expressed in the heart, skeletal muscles, adipose tissues, and macrophages ( 14, 15 ). However, its levels are barely detectable in the liver under normal conditions. VLDLR mediates the uptake of VLDL by peripheral tissues through LPL-dependent lipolysis or receptor-mediated endocytosis (16)(17)(18)(19), and thus Abstract The liver and the VLDL receptor (VLDLR) play major roles in TG and VLDL metabolism. However, the exact role of liver VLDLR is not well known because of the absence of or diffi culty in detecting VLDLR in the liver. In this study, we demonstrate that fenofi brate, a PPAR␣ agonist and widely used TG-lowering drug, markedly upregulated hepatic VLDLR, which is essential for lowering TG. This study also shows that the distinct regulatory roles of PPAR␣ agonists on VLDLR in the liver and peripheral tissues including adipose tissues, heart, and skeletal muscles are due to the pattern of expression of PPAR␣. The in vivo portion of our study demonstrated that oral fenofi brate robustly increased liver VLDLR expression levels in hyperlipidemic and diabetic mice and signifi cantly reduced the increase in serum TG observed in wt mice after feeding with high-fat diet (HFD) but not in Vldlr ؊ / ؊ mice or Ppar␣ Dyslipidemia is considered one of the major risk factors for the pathogenic progression of many diseases, including CVD...

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Section: Discussionsupporting

confidence: 92%

Upregulation of hepatic VLDLR via PPARα is required for the triglyceride-lowering effect of fenofibrate

Gao

Shen

et al. 2014

Journal of Lipid Research

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“…In addition to the already established effects of OA on the hepatic accumulation of fat, this study revealed an increased activity of functional and total cardiac LPL, data that corroborated our previous results from epididymal fat tissue (Ferreira et al, 2008). The high lipoprotein lipase activity induced by OA intake, apart from increasing the energy supply to cardiac tissue, may also contribute to clearance of serum fat.…”

Section: Discussionsupporting

confidence: 91%

“…Wistar male rats (8-10 weeks old) were obtained from the Breeding Center of the Federal University of Minas Gerais (UFMG); kept in individual cages in an environmentally controlled room with a 14/10 h light/dark cycle and had free access to tap water and food. The animals were divided into 2 experimental groups -1) fed with a balanced diet (C -control group) consisting of 58% carbohydrate (29% starch and 29% sucrose), 7% corn oil, 18% casein, 4% salts, 1% vitamins and 12% humidity (Kettelhut et al, 1980); and 2) fed with a balanced diet supplemented with 1% OA (OA group) -which were fed during 9 days (Ferreira et al, 2008), after 2 days of adaptation to these diets. The OA administration has been reported to be effective in reducing the extent of the infarcted area in rats (Ferdinandy et al, 1998;Munsch et al, 1989;Rosenfeldt, 1998).…”

Section: Animals and Treatmentmentioning

confidence: 99%

Improvement of the energy supply and contractile function in normal and ischemic rat hearts by dietary orotic acid

et al. 2012

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Thus, in orotic acid hearts there was a simultaneous stimulus of fatty acid oxidation and glycolytic pathway, reflected in increased energetic content even in pre-ischemia. The analysis of the cardiac contractility index showed a positive inotropic effect of orotic acid due, at least in part, to the increased availability of energy. The result allows us to suggest that the metabolic changes induced by orotic acid result in appreciable alterations on myocardial contractile function.

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“…Peroxisome proliferator-activated receptors (PPAR) belonging to the nuclear receptors superfamily are ligand-activated transcriptional factors that may regulate the expressions of numerous genes involved in glucose and lipid homeostasis (Desvergne & Wahli 1999). In recent years, several well-known PPARa/g agonists, such as lipid-lowering (fibrates) and insulin-sensitizing (thiazolidinediones) drugs, showed the beneficial effects on improving fatty liver and IR (Neuschwander-Tetri et al 2003;FernandezMiranda et al 2008;Ferreira et al 2008). Therefore, lipanthyl (a PPARa agonist) and rosiglitazone (a PPARg agonist) were acted as the positive drugs in the experiment.…”

Section: Introductionmentioning

confidence: 99%

Osthole improves glucose and lipid metabolism via modulation of PPARα/γ-mediated target gene expression in liver, adipose tissue, and skeletal muscle in fatty liver rats

Zhao

Zhong

et al. 2015

Pharmaceutical Biology

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Context: Osthole may be a dual agonist of peroxisome proliferator-activated receptors (PPAR) a/g and ameliorate the insulin resistance (IR), but its mechanisms are not yet understood completely. Objective: We investigated the effects of osthole on PPARa/g-mediated target genes involved in glucose and lipid metabolism in liver, adipose tissue, and skeletal muscle in fatty liver and IR rats. Materials and methods: The rat model was established by orally feeding high-fat and high-sucrose emulsion for 9 weeks. The experimental rats were treated with osthole 5-10 mg/kg by gavage after feeding the emulsion for 6 weeks, and were sacrificed 4 weeks after administration. Results: After treatment with osthole 5-10 mg/kg for 4 weeks, the lipid levels in serum and liver were decreased by 37.9-67.2% and 31.4-38.5% for triglyceride, 33.1-47.5% and 28.5-31.2% for free fatty acid, respectively, the fasting blood glucose, fasting serum insulin, and homeostasis model assessment of IR were also decreased by 17.2-22.7%, 25.9-26.7%, and 37.5-42.8%, respectively. Osthole treatment might simultaneously decrease the sterol regulatory element binding protein1c, diacylglycerol acyltransferase, and fatty acid synthase mRNA expressions in liver and adipose tissue, and increase the carnitine palmitoyltransferase-1A mRNA expression in liver and glucose transporter-4 mRNA expression in skeletal muscle, especially in the osthole 10 mg/kg group (p50.01). Discussion and conclusion: Osthole can improve glucose and lipid metabolism in fatty liver and IR rats, and its mechanisms may be associated with synergic modulation of PPARa/g-mediated target genes involved in glucose and lipid metabolism in liver, adipose tissue, and skeletal muscle. ARTICLE HISTORY

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Fenofibrate prevents orotic acid—Induced hepatic steatosis in rats

Cited by 20 publications

References 52 publications

Upregulation of hepatic VLDLR via PPARα is required for the triglyceride-lowering effect of fenofibrate

Upregulation of hepatic VLDLR via PPARα is required for the triglyceride-lowering effect of fenofibrate

Improvement of the energy supply and contractile function in normal and ischemic rat hearts by dietary orotic acid

Osthole improves glucose and lipid metabolism via modulation of PPARα/γ-mediated target gene expression in liver, adipose tissue, and skeletal muscle in fatty liver rats

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