Activation of PPARalpha and PPARgamma reduces triacylglycerol synthesis in rat hepatoma cells by reduction of nuclear SREBP-1.

Fibrates and thiazolidinediones, agonists of PPARalpha and PPARgamma, respectively, reduce triglyceride concentrations in rat liver and plasma. Fatty acid and triacylglycerol synthesis in mammals is regulated by sterol regulatory element-binding protein (SREBP)-1c. Recently, it was shown that insulin-induced gene (Insig)-1, the key regulator of SREBP activity, is up-regulated by both activation of PPARalpha and PPARgamma. In order to elucidate whether inhibition of SREBP-1 activation may contribute to the triacylglycerol lowering effect of PPARalpha and PPARgamma agonists, we incubated rat hepatoma Fao cells with WY 14,643 and troglitazone, strong and selective agonists of PPARalpha and PPARgamma, respectively. Activation of both, PPARalpha and PPARgamma led to increased concentrations of Insig-1 and Insig-2a, with the most prominent effect on Insig-2a after troglitazone incubation. As a result, the amount of nuclear SREBP-1 was reduced in Fao cells by both WY 14,643 and troglitazone treatment. The reduction of nuclear SREBP-1 was associated with decreased mRNA concentrations of its target genes fatty acid synthase and glycerol-3-phosphate acyltransferase, implicated in fatty acid and triacylglycerol synthesis. This was finally reflected in reduced rates of newly synthesized triacylglycerols from de novo-derived fatty acids and decreased intracellular and secreted triacylglycerol concentrations in Fao cells treated with WY 14,643 and troglitazone, respectively. Thus, these data suggest that the triacylglycerol reducing effect of fibrates and thiazolidinediones is partially caused by inhibition of SREBP-1 activation via up-regulation of Insig.