Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice.

AIMS/INTRODUCTION: Peroxisome proliferator-activated receptor-α (PPARα) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARα agonists. MATERIALS AND METHODS: To compare the effects of K-877 on PPARα transcriptional activity with those of the classical PPARα agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARα transactivation luciferase assay was carried out. WT and Ppara-/- mice were fed with a moderate-fat (MF) diet for 6 days, and methionine-choline-deficient (MCD) diet for 4 weeks containing Feno or K-877. RESULTS: In luciferase assays, K-877 activated PPARα transcriptional activity more efficiently than the classical PPARα agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K-877 effects were blunted in Ppara-/- mice, confirming that K-877 activates PPARα. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes. CONCLUSIONS: The present data show that K-877 is an attractive PPARα-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism.

Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling.

Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors that form obligate heterodimers with retinoid X receptors (RXRs). These nuclear receptors play crucial roles in the regulation of fatty acid metabolism: LXRs activate expression of sterol regulatory element-binding protein 1c (SREBP-1c), a dominant lipogenic gene regulator, whereas PPARalpha promotes fatty acid beta-oxidation genes. In the current study, effects of PPARs on the LXR-SREBP-1c pathway were investigated. Luciferase assays in human embryonic kidney 293 cells showed that overexpression of PPARalpha and gamma dose-dependently inhibited SREBP-1c promoter activity induced by LXR. Deletion and mutation studies demonstrated that the two LXR response elements (LXREs) in the SREBP-1c promoter region are responsible for this inhibitory effect of PPARs. Gel shift assays indicated that PPARs reduce binding of LXR/RXR to LXRE. PPARalpha-selective agonist enhanced these inhibitory effects. Supplementation with RXR attenuated these inhibitions by PPARs in luciferase and gel shift assays, implicating receptor interaction among LXR, PPAR, and RXR as a plausible mechanism. Competition of PPARalpha ligand with LXR ligand was observed in LXR/RXR binding to LXRE in gel shift assay, in LXR/RXR formation in nuclear extracts by coimmunoprecipitation, and in gene expression of SREBP-1c by Northern blot analysis of rat primary hepatocytes and mouse liver RNA. These data suggest that PPARalpha activation can suppress LXR-SREBP-1c pathway through reduction of LXR/RXR formation, proposing a novel transcription factor cross-talk between LXR and PPARalpha in hepatic lipid homeostasis.