t0901317 and Hyperlipidemias

Liver X receptors (LXRα and LXRβ) are ligand-activated transcription factors that regulate expression of genes involved in lipid and cholesterol metabolism. LXR expression has been identified in human and rodent cardiac tissue, however, its role in this tissue remains unclear. The aim of this study was to investigate effects of in vivo LXR activation on lipid metabolism in the rat myocardium under the conditions of low and high lipid intake.. The experiments were performed on male Wistar rats fed for 5 weeks on either low fat diet (LFD) or high fat diet (HFD). Next, the animals were randomly divided into two groups receiving either LXR agonist - T0901317 (10mg/kg/d) or vehicle for the last week of the experiment. After anesthesia samples of the left ventricle and blood were taken.. It was found that LXRβ is the dominant isoform in the rat myocardium and the expression of both LXR isoforms did not change after administration of T0901317. Agonist treatment induced hyperlipidemia in low fat fed rats and this effect was amplified in high fat fed rats. LXR agonist elevated content of myocardial triacylglycerols in animals fed on LFD and content of phospholipids in animals fed on HFD. Levels of the remaining examined lipid classes (nonesterified fatty acids, diacylglycerol, free cholesterol, cholesterol esters, ceramide) was decreased or unchaged after LXR activation.. We conclude that administration of T0901317 does not lead to severe myocardial lipid accumulation in rats despite of its high plasma availability.

Topics: Animals; Diet, High-Fat; Heart Ventricles; Humans; Hydrocarbons, Fluorinated; Hyperlipidemias; Lipid Metabolism; Liver X Receptors; Male; Myocardium; Orphan Nuclear Receptors; Rats; Sulfonamides

Liver X receptors (LXRs) are ligand-activated transcription factors that were shown to stimulate hepatic lipogenesis leading to liver steatosis and hypertriglyceridemia. Despite their pro-lipogenic action, LXR activators normalize glycemia and improve insulin sensitivity in rodent models of type 2 diabetes. Antidiabetic action of LXR agonists is thought to result from suppression of hepatic gluconeogenesis. However, it remains unclear whether LXR activation affects muscle insulin sensitivity. In the present study we attempted to answer this question.. The experiments were performed on male Wistar rats fed for 5 weeks on either standard chow or high fat diet. The latter group was further divided into two subgroups receiving either selective LXR agonist - T0901317 (10mg/kg/d) or vehicle during the last week of the experiment. All animals were then anaesthetized and samples of the soleus as well as red and white sections of the gastrocnemius muscle were excised.. As expected, administration of T0901317 to high-fat fed rats augmented diet-induced hyperlipidemia. Nevertheless, it also normalized glucose tolerance and improved insulin-stimulated glucose uptake in isolated soleus muscle. In addition, LXR agonist completely restored glucose transporter 4 expression and insulin-stimulated Akt substrate of 160 kDa phosphorylation in all investigated muscles. Insulin-sensitizing effect of T0901317 was not related to changes in intramuscular level of lipid mediators of insulin resistance, since neither diacylglycerols nor ceramide content was affected by the treatment.. We conclude that improvement in muscle insulin sensitivity is one of the mechanisms underlying the antidiabetic action of LXR activators.

Topics: Animals; Ceramides; Diet, High-Fat; Diglycerides; Glucose Tolerance Test; Glucose Transporter Type 1; Glucose Transporter Type 4; GTPase-Activating Proteins; Hydrocarbons, Fluorinated; Hyperlipidemias; Insulin; Liver X Receptors; Male; Muscle, Skeletal; Orphan Nuclear Receptors; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Sulfonamides

Angiopoietin-like protein 3 (Angptl3)-lipoprotein lipase (LPL) pathway may be a useful pharmacologic target for hyperlipidemia. The present study was conducted to test the effect of soluble fiber extracted from Undaria pinnatifida (UP), on hyperlipidemia in apolipoprotein E-deficient (ApoE(-/-)) mice. Forty mice were divided into four groups (n = 10): control group (C57BL/6J mice), ApoE(-/-) mice group, and two groups of ApoE(-/-) mice treated with UP fiber (5 or 10 % per day). UP soluble fiber treatment significantly decreased plasma and hepatic total cholesterol, triglycerides levels, plasma low-density lipoprotein cholesterol, and malondialdehyde concentrations and increased plasma high-density lipoprotein cholesterol level and downregulated protein expression of Angptl3 concomitantly with upregulated protein expression of LPL. In addition, T0901317 caused elevated expression of hepatic Angptl3 protein, and the effect of T0901317 was also abrogated by UP soluble fiber in C57BL/6J mice. The present results suggest that the UP soluble fiber regulates Angptl3-LPL pathway to lessen hyperlipidemia in mice.

Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Animals; Anticholesteremic Agents; Apolipoproteins E; Cholesterol, HDL; Cholesterol, LDL; Dietary Fiber; Gene Expression Regulation; Hydrocarbons, Fluorinated; Hyperlipidemias; Lipoprotein Lipase; Liver; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; Solubility; Sulfonamides; Triglycerides; Undaria

Fenofibrate, a PPAR-α agonist and rosiglitazone, a PPAR-γ agonist, reduce triglycerides and fatty acids in humans and in animal disease models. The efficacy of PPAR-α agonists in mouse model of human atherosclerosis disease has shown mixed results, and efficacy of PPAR-γ and liver X receptor (LXR) agonists has not been evaluated in cholesterol ester transfer protein (CETP) producing animal models.. The efficacy of PPAR-α, PPAR-γ and LXR agonists on lipid lowering and antiatherosclerotic activities was studied in atherosclerosis-susceptible F(1)B hamster that showed greater responsiveness to dietary fat and cholesterol (HFHC) diet and increased severity of atherosclerosis compared to Golden Syrian (GS) hamsters (aortic lesion 0.3% in GS vs 5% in F(1)B). F(1)B hamsters were fed HFHC diet and simultaneously treated with fenofibrate, rosiglitazone, and T0901317 (a pan LXR agonist) for 8 weeks. Fenofibrate lowered triglycerides and LDL-C by >80%, rosiglitazone did not significantly impact plasma lipid levels, and as expected, T0901317 increased triglycerides by 3-fold and HDL-C by 50%. The lesions in the aortic arch area as measured by en face method, decreased by 81%, 38% and 35%, following fenofibrate, rosiglitazone, and T0901317 treatments, respectively. In F(1)B hamster regression model, fenofibrate decreased levels of triglycerides and LDL-C by >85%, and LDL-C by >70%, respectively, which resulted in ∼50% regression of aortic lesions compared to vehicle treated group, and ∼36% compared to baseline.. These results demonstrate that: (a) F(1)B hamster is more sensitive to developing diet-induced hyperlipidemia and atherosclerosis; and (b) the greater antiatherosclerotic efficacy of fenofibrate occurred primarily via reductions in proatherogenic lipoproteins. Thus, PPAR-α selective agonist shows a greater anti-atherosclerotic response compared to PPAR-γ and LXR agonists in diet-induced atherosclerosis-susceptible F(1)B hamster.

Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol; Cricetinae; Fatty Acids; Female; Fenofibrate; Hydrocarbons, Fluorinated; Hyperlipidemias; Liver X Receptors; Male; Mesocricetus; Orphan Nuclear Receptors; PPAR alpha; PPAR gamma; Rosiglitazone; Sulfonamides; Thiazolidinediones; Triglycerides

Fenofibrate and rosiglitazone are prescribed to treat hypertriglyceridemia and diabetes, respectively. Since fenofibrate improves lipid profile in diabetic patients and improves insulin resistance in animal models, we examined the mechanism of antidiabetic effects of fenofibrate in KKAy mouse, an animal model of diabetes and dyslipidemia. KKAy mice were treated with fenofibrate, rosiglitazone, liver x receptor agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317), and a combination of fenofibrate and T090317 for 2 weeks. Fenofibrate lowered serum triglycerides by 90% and free fatty acid (FFA) by 50% via inhibition of hepatic fatty acid synthesis. Fenofibrate also prevented T0901317-induced increases of triglycerides by dampening T090317-mediated sterol response element binding protein 1c (SREBP1c) up-regulation. Glucose lowering was comparable (approximately 40%) in fenofibrate and rosiglitazone treated mice. T090317 also showed mild reduction in serum glucose, in part, via down-regulation of phosphoenol pyruvate carboxykinase (PEPCK). Combining fenofibrate with T0901317 caused greater reduction in serum glucose, suggesting an additive effect. The mechanism of lipid and glucose lowering in KKAy mice was examined. Liver PEPCK showed down-regulation in all treatment groups with fenofibrate showing greater effects. Combination of fenofibrate with T090317 showed additive effects on PEPCK down-regulation. Fenofibrate decreased hepatic diacyl glycerol acyl transferase 2 (DGAT2) mRNA leading to reduction in triglyceride synthesis. Most importantly, fenofibrate down regulated expression of hepatic and adipose 11beta hydroxysteroid dehydrogenase (11beta-HSD1) gene, which contributed in attenuating diabetic state. Thus, amelioration of antidiabetic and hyperlipidemic state by fenofibrate in KKAy mice occurred via down-regulation of DGAT2, PEPCK and 11beta-HSD1. It is also shown that the undesirable lipogenic effects of T090317 could be dampened by fenofibrate.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diacylglycerol O-Acyltransferase; DNA-Binding Proteins; Down-Regulation; Drug Interactions; Fenofibrate; Hydrocarbons, Fluorinated; Hyperlipidemias; Hypolipidemic Agents; Liver X Receptors; Male; Mice; Orphan Nuclear Receptors; Phosphoenolpyruvate Carboxykinase (GTP); PPAR alpha; PPAR gamma; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Sulfonamides; Thiazolidinediones; Triglycerides