Nonalcoholic steatohepatitis (NASH) is one of the most frequent causes of abnormal liver dysfunction associated with synthesis and oxidation of fatty acids. Adiponectin receptors (AdipoR1/R2) and insulin receptor substrates (IRS-1/-2) are known as modulators of these fatty acid metabolisms in the liver; however, the regulatory roles of these receptors in the synthesis and oxidation of fatty acids are unclear in the liver of NASH. In this study, we examined the roles of hepatic AdipoR1/R2 and IRS-1/-2 in NASH using an animal model. After feeding a high-fat and high-cholesterol diet to obese fa/fa Zucker rats for 8 weeks, rats showed fatty liver spontaneously with inflammation and fibrosis that are characteristic of NASH. The expression levels of AdipoR1/R2 and IRS-2 were significantly decreased, whereas IRS-1 was significantly increased, in NASH. As a result of the decrease of AdipoR1/R2 expression, the messenger RNA expression levels of genes located downstream of AdipoR1/R2, adenosine monophosphate-activated protein kinase α1/α2, which inhibits fatty acid synthesis, and peroxisome proliferator-activated receptor α, which activates fatty acid oxidation, also decreased. Expression level of sterol regulatory element binding protein-1c was found to be elevated, suggesting the up-regulation of IRS-1, and resulted in increased fatty acid synthesis. Furthermore, increase of forkhead box protein A2 expression was observed, which might be associated with the down-regulation of IRS-2, facilitating fatty acid oxidation. Taken together, increased synthesis and oxidation of fatty acids by up- or down-regulation of AdipoR or IRS may contribute to the progression of NASH. Thus, AdipoR and IRS might be crucially important regulators for the synthesis and oxidation of fatty acids in the liver of NASH.
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