Hepatic PGC-1β overexpression induces combined hyperlipidemia and modulates the response to PPARα activation

Objective - Previous studies have indicated that the hyperlipidemia and gene expression changes induced by a short-term high-fat diet (HFD) are mediated through the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 beta, and that in vitro both PGC-1 beta and PGC-1 alpha increase PPAR alpha-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPAR alpha agonist Wy14,643 (Wy). Methods and Results - C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1 alpha or PGC-1 beta. On chow, hepatic PGC-1 beta overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPAR alpha and hepatic lipase mRNA levels were reduced. PGC-1 beta overexpression blunted Wy-mediated changes in expression levels of PPAR alpha and downstream genes. Furthermore, PGC-1 beta did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1 beta and PGC-1 beta overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1 beta overexpression decreased hepatic SREBP-1c, yet increased FAS and ACC alpha mRNA and plasma triglyceride levels. Conclusions - Hepatic PGC-1 beta overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1 beta overexpression reduced the potentially beneficial effects of PPAR alpha activation on gene expression. Thus, inhibition of hepatic PGC-1 beta may provide a therapy for treating combined hyperlipidemia.