Role of liver PPARγ in high fat diet-induced hepatic steatosis
Dept. of Medical Science/박사
Recently, it has been implied that hepatic peroxisome proliferator activated receptor γ (PPARγ) plays a role in hepatic lipid accumulation. I found that C3H/HeJ mice barely express PPARγ in the liver and are highly resistant to hepatic steatosis in response to a high-fat diet (HFD), as compared to the diet-induced obesity-prone model, C57BL/6 mice. The expression of hepatic PPARγ2 was low in C57BL/6 mice fed a normal chow diet, and was increased robustly when mice were fed a HFD. As a result, hepatic triacylglycerol (TG) and cholesterol levels were significantly increased by HFD, and oil-red O staining demonstrated development of hepatic steatosis. In contrast, the liver of C3H/HeJ mice remained normal without accumulation of lipid droplets on HFD. In addition, C3H/HeJ mice did not develop glucose intolerance, showing a normal glucose tolerance test even after feding HFD. Adenovirus-mediated expression of PPARγ2 in primary hepatocytes isolated from C3H/HeJ mice resulted in increased lipid accumulation, as determined by fatty acid transport and TG contents. Adenoviral overexpression of PPARγ2 in C3H/HeJ mice resulted in a significant accumulation of lipids in the liver as similar as in primary hepatocyte. I also found that hepatic PPARγ2 up-regulated several target genes including aP2/422, FAT/CD36, and monoacylglycerol O-acyltransferase 1 (MGAT1) in the liver. In particular, MGAT1 expression was tightly associated with PPARγ2 expression, indicating that hepatic PPARγ2 is responsible for the fatty liver through an MGAT1-involved pathway in lipid metabolism. Acetylation and methylation analyses of PPARg2 gene showed decreased acetylation status in C3H/HeJ mice but no difference in methylation between C3H/HeJ and C57BL/6 liver. This result suggests that epigenetics and other mechanisms are involved in regulation of the expression of PPARγ in C3H/HeJ mice liver. Taken together, it is suggested that increased PPARg activity on HFD plays a major role in lipid accumulation in liver, by regulating fatty acid transport and the TG incorporation pathway.