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Keywords:

  • insulin resistance;
  • nonalcoholic fatty liver;
  • peroxisome proliferator-activated receptors;
  • tumor necrosis factor

Abstract

Background and Aims:  In a previous study, the authors found that reduced expression of peroxisome proliferator-activated receptor (PPAR)-α might play an important role in developing nonalcoholic fatty liver disease (NAFLD). The aim of this study was to analyze the effects of PPAR-α and -γ agonists on NAFLD and verify the mechanisms underlying the PPAR-α and -γ agonist-induced improvements by evaluating the hepatic gene expression profile involved in fatty-acid metabolism, using the Otsuka–Long Evans–Tokushima fatty (OLETF) rat.

Methods:  Rats were assigned to a control group (group I), fatty liver group (group II), PPAR-α agonist treatment group (group III), or PPAR-γ agonist treatment group (group IV). Fasting blood glucose, total cholesterol, and triglycerides were measured. Liver tissues from each group were processed for histological and gene expression analysis. mRNAs of enzymes involved in fatty-acid metabolism and tumor necrosis factor (TNF)-α were measured.

Results:  After 28 weeks treatment with PPAR-α or -γ agonist, steatosis of the liver was improved in groups III and IV compared with group II. Fasting blood glucose levels were significantly lower in groups III and IV than in group II. In group III, mRNA expression of fatty-acid β-oxidation enzymes, such as fatty-acid transport protein (FATP), fatty-acid binding protein, carnitine palmitoyltransferase II, medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase, was significantly increased. However, the treatment-induced modulation of fatty-acid β-oxidation enzymes was confined to FATP and MCAD in group IV. TNF-α tended to be reduced in groups III and IV compared with group II.

Conclusions:  Treatment with PPAR agonists, especially a PPAR-α agonist, improved the histological and biochemical parameters in the OLETF rat model by inducing fatty-acid metabolic enzymes.