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- Title
Protective Effect of KRP-101, Novel PPARα Agonist, on Fatty Liver Disease Through Induction of Lipid Oxidation & Suppression of Lipogenesis in Hamsters.
- Authors
Kobayashi, Naoki; Tsunoda, Masaki; Nagasawa, Michiaki; Akasaka, Yunike; Ide, Tomohiro; Murakami, Koji
- Abstract
PPARα is abundantly expressed in liver and play a crucial role in lipid oxidation. Thus, we studied the effect of PPARα agonist on fatty liver disease often associated with obesity and insulin resistance. In hamsters fed a high fat diet (HFD) for 2 wk, KRP-101 (KRP; a novel potent PPARα agonist) and Fenofibrate (FF; a known weak PPARα agonist) were administered for 2 wk while HFD continued. HFD caused hepatic triglyceride (TG) accumulation, increased lipogenie activity (fatty acid production from [[sup 14]C]-acetate) and decreased fatty acid oxidation (CO[sub 2] production from [[sup 14]C]-palmitic acid), compared to standard diet (SD). KRP (0.1, 0.3, and 1 mg/kg/day) significantly lowered hepatic and serum TG levels (-21, -42, -47% and -42, -51, -52%, respectively). FF (300 mg/kg/day) did not significantly affect hepatic TG levels, while serum TG levels decreased (-44%). To investigate the mechanism of the anti-fatty liver effect of KRP, lipogenic and lipid oxidative activities were measured in the livers of KRP-treated hamsters. KRP (0.1, 0.3, and 1 mg/kg/day) decreased hepatic lipogenesis and increased hepatic lipid oxidation (-21, -33, -43% and 1.3, 2.4, 2.5-fold, respectively). To elucidate whether the anti-lipogenic action of KRP involves direct action on the liver, lipogenesis in primary hamster hepatocytes was studied. KRP (0.1-10 µM) decreased lipogenesis in hepatocytes in a concentration-dependent manner, whereas fenofibric acid (1-100 µM), an in vivo active metabolite of FF, had no effect. KRP did not affect gene expressions of fatty acid synthase or acetyl-CoA carboxylase (ACC), major lipogenic enzymes. KRP significantly increased Ser-79 phosphorylation of ACC, suggesting that KRP inhibited ACC activity. When PPARα was down-regulated by PPARα siRNA treatment, the anti-lipogenic action of KRP was not changed. These findings show that KRP potently inhibits fat-induced fatty liver disease in hamsters. Our data suggest that the unique action of KRP may be mediated by PPARα-dependent (increased lipid oxidation) and -independent (suppression of lipogenesis) mechanisms.
- Publication
Diabetes, 2007, Vol 56, pA131
- ISSN
0012-1797
- Publication type
Academic Journal