Hepatic PGC-1� overexpression induces combined hyperlipidemia and modulates the response to PPAR� 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 coactivator (PGC)-1, and that in vitro both PGC-1 and PGC 1 increase PPAR-mediated transcriptional activities. Here, we examined the in vivo effects of these two coactivators in potentiating the lipid lowering properties of the PPAR agonist Wy14,643 (Wy). Methods and Results—C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1 or PGC-1. On chow, hepatic PGC-1 overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPAR and hepatic lipase mRNA levels were reduced. PGC-1 overexpression blunted Wy-mediated changes in expression levels of PPAR and downstream genes. Furthermore, PGC-1 did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1 and PGC-1 overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1 overexpression decreased hepatic SREBP-1c, yet increased FAS and ACC mRNA and plasma triglyceride levels. Conclusions—Hepatic PGC-1 overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1 overexpression reduced the potentially beneficial effects of PPAR activation on gene expression