Up-regulation of Hepatic VLDLR via PPARa Is Required for the Triglyceride-Lowering Effect of Fenofibrate

The liver and VLDLR play major roles in VLDL metabolism; however, the exact role of liver VLDLR is not well known because of difficulty in detecting VLDLR in the liver. The in vivo portion of our study demonstrated that oral fenofibrate robustly increased liver VLDLR expression levels in hyperlipidemic and diabetic mice models. The administration of fenofibrate significantly reduced the increase in serum TG observed in mice after feeding with HFD. This effect was not observed in Vldlr -/- mice or Ppara -/-mice. The in vitro portion of our study showed that fenofibrate increased the VLDLR levels and the binding of VLDLR and VLDL in primary cultured liver cells but not in cells with the deletion of PPARa. The activation of PPARa with PPARa specific agonist increased VLDLR expression in HepG2 cells; this increase was inhibited by GW6471, a PPARa specific antagonist. Moreover, PPARa up-regulates liver VLDLR transcriptional activity through PPRE binding to the VLDLR promoter. These results indicate a distinct regulatory role of PPARa agonists on VLDLR in the liver and peripheral tissues and suggest that up-regulated hepatic VLDLR by PPARa agonists is essential for lowering TG, providing a novel mechanism for the TG-lowering effects of fenofibrate in dyslipidemia.