PPARs in the regulation of gene expression and lipid metabolism in the liver

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, regulating genes involved in carbohydrate, lipid and lipoprotein metabolism. Synthetic PPARalpha agonists used in clinic are the fibrates, and their hypotriglyceridemic effect is believed to be the result of decreased VLDL triglyceride secretion and increased turnover of triglyceride-rich lipoprotein particles in the circulation. Synthetic PPARgamma agonists, used in clinic to treat type 2 diabetes, are the thiazolidinediones (TZDs), and PPARgamma in adipose tissue is believed to be the primary target for the TZDs.TZD treatment of obese mice resulted in increased expression of proteins taking part in the peroxisomal fatty acid beta-oxidation in the liver, whereas this effect was abolished in lean mice. This difference in effect might be explained by the finding that obese mice expressed higher levels of PPARgamma2 in the liver as compared to the lean mice. In primary mouse hepatocyte cultures, insulin and oleic acid were shown to increase the level of PPARgamma2, whereas PPARgamma1 expression was unaffected. The stimulatory effect of insulin on PPARgamma2 transcription was mediated via the phosphatidylinositol 3-kinase pathway. Both in vitro, in cultured hepatocytes, and in vivo, treatment with the PPARalpha agonist Wy14,643 (Wy) resulted in increased expression and activity of microsomal triglyceride transfer protein (MTP), which is rate limiting in the VLDL assembly and secretion. Increased MTP expression was paralleled by increased apoB100 secretion, suggesting that the stimulatory effect of Wy on apoB100 secretion could be mediated via increased MTP expression. Wy was also shown to increase the hepatic expression of adipose differentiation-related protein (ADRP) in vivo in mice and in vitro in cultured mouse hepatocytes. Wy increased the hepatic triglyceride content despite increased fatty acid oxidation and unchanged triglyceride synthesis. However, Wy was shown to inhibit the triglyceride secretion, which might contribute to the cellular triglyceride accumulation. Similar to Wy incubation, ADRP overexpression in mouse hepatocytes resulted in decreased triglyceride secretion and increased cellular triglyceride mass. In ADRP overexpressing cells, Wy further inhibited the triglyceride secretion although the ADRP protein expression was unaltered. Since the triglyceride content was unaffected by Wy in ADRP overexpressing cells, incubation with Wy did not result in lack of cellular triglycerides for VLDL secretion. Rather, PPAR Ñ activation prevents the availability of triglycerides for VLDL assembly, in part by increasing the expression of ADRP.In summary, this study shows that the diabetes-associated increase in hepatic PPARgamma2 could be due to increased insulin signaling, and important for the effects of PPARgamma agonists in liver. Moreover, PPARalpha activation influences hepatic expression of MTP and ADRP that contributes to the increased secretion of triglyceride-poor apoB-containing lipoproteins following PPARalpha activation