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

Figures

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  Figure 1. K‐877 activates the Peroxisome proliferator‐activated receptor‐α (PPARα) transcriptional activity. (a,b) HepG2 cells were co‐transfected with GAL4 UAS‐LUC and pM GAL4‐hPPARα ligand‐binding domain vectors, and with a pRL‐SV40 plasmid as a reference in 24‐well plates for 24 h. Cells were then treated with Wy, Feno or K‐877 for 48 h, and were harvested at 48 h after transfection. Luciferase activity was measured and normalized to that of Renilla luciferase activity. (a) Dose–response curves of PPARα transactivation. (b) Cells were then treated with Wy14643 (Wy; 50 μmol/L), fenofibrate (Feno; 30 μmol/L) or K‐877 (50 nmol/L); n = 8 per group. (c) AML12.2 cells were treated with Feno (50 μmol/L) or K‐877 (5 and 50 μmol/L) for 48 h. Fgf21 expression was determined by quantitative polymerase chain reaction; n = 9 per group, *P < 0.05 and **P < 0.01.

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  Figure 2. K‐877 reduces plasma lipid levels and increases the expression of hepatic fatty acid oxidation genes in wild type, but not in Ppara −/− mice. Eight‐week old male wild‐type (WT) and Ppara −/− mice were administrated with fenofibrate (Feno; 0.2%) or K‐877 (0.001%) for 6 days. (a) Plasma triglyceride, total cholesterol and non‐esterified fatty acid (NEFA) levels, and (b) hepatic gene expression in WT and Ppara −/− mice; n = 9–13 per group; *P < 0.05 and **P < 0.01. mRNA, messenger ribonucleic acid.

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  Figure 3. K‐877 suppresses methionine–choline‐deficient (MCD) diet‐induced non‐alcoholic fatty liver disease in wild‐type (WT), but not in Ppara −/− mice. Eight‐week‐old male WT and Ppara −/− mice were fed moderate‐fat (MF) or MCD diets containing fenofibrate (Feno; 0.1%) or K‐877 (0.00025%) for 4 weeks. Hematoxylin–eosin staining in the (a) liver, (b) hepatic lipid contents, and (c) plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined in WT and Ppara −/− mice; n = 5–10 per group, *P < 0.05 and **P < 0.01. TC, total cholesterol; TG, triglyceride.

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  Figure 4. Hepatic gene expression in wild‐type (WT) and Ppara −/− mice fed the methionine–choline‐deficient (MCD) diet with K‐877 or fenofibrate (Feno) for 4 weeks. Eight‐week‐old male WT and Ppara −/− mice were fed moderate‐fat (MF) or MCD diets containing Feno (0.1%) or K‐877 (0.00025%) for 4 weeks. Hepatic gene expression profiles of WT and Ppara −/− mice; n = 5–10 per group; *P < 0.05 and **P < 0.01. mRNA, messenger ribonucleic acid.