Methods and Results— C57BL/6 mice were fed chow or HFD and transduced with adenoviruses encoding PGC-1α or PGC-1β. On chow, hepatic PGC-1β overexpression caused severe combined hyperlipidemia including elevated plasma apolipoprotein B levels. Hepatic triglyceride secretion, DGAT1, and FAT/CD36 expression were increased whereas PPARα and hepatic lipase mRNA levels were reduced. PGC-1β overexpression blunted Wy-mediated changes in expression levels of PPARα and downstream genes.
Furthermore, PGC-1β did not potentiate Wy-stimulated fatty acid oxidation in primary hepatocytes. PGC-1β and PGC-1α overexpression did not alter SREBP-1c, SREBP-1c target gene expression, nor hepatic triglyceride content. On HFD, PGC-1β overexpression decreased hepatic SREBP-1c, yet increased FAS and ACCα mRNA and plasma triglyceride levels.
Conclusions— Hepatic PGC-1β overexpression caused combined hyperlipidemia independent of SREBP-1c activation. Hepatic PGC-1β overexpression reduced the potentially beneficial effects of PPARα activation on gene expression. Thus, inhibition of hepatic PGC-1β may provide a therapy for treating combined hyperlipidemia.
The effects of increased hepatic expression of PGC-1α or PGC-1β on PPARα activation, gene expression, and lipid metabolism were investigated. PGC-1β overexpression induced a combined hyperlipidemia and blunted the effects of PPARα activation on gene expression.
Thus, inhibition of hepatic PGC-1β may ameliorate combined hyperlipidemia and improve the effects of PPARα activators.
|Journal||Arteriosclerosis, Thrombosis, and Vascular Biology|
|Publication status||Published - 2007|
|MoE publication type||A1 Journal article-refereed|
- apolipoprotein B
- hepatic lipase