Upregulation of hepatic VLDLR via PPARα is required for the triglyceride-lowering effect of fenofibrate.

The liver and the VLDL receptor (VLDLR) play major roles in TG and VLDL metabolism. However, the exact role of liver VLDLR is not well known because of the absence of or difficulty in detecting VLDLR in the liver. In this study, we demonstrate that fenofibrate, a PPARα agonist and widely used TG-lowering drug, markedly upregulated hepatic VLDLR, which is essential for lowering TG. This study also shows that the distinct regulatory roles of PPARα agonists on VLDLR in the liver and peripheral tissues including adipose tissues, heart, and skeletal muscles are due to the pattern of expression of PPARα. The in vivo portion of our study demonstrated that oral fenofibrate robustly increased liver VLDLR expression levels in hyperlipidemic and diabetic mice and significantly reduced the increase in serum TG observed in wt mice after feeding with high-fat diet (HFD) but not in Vldlr(-/-) mice or Pparα(-/-) mice. However, overexpression of mouse VLDLR in livers of Vldlr(-/-) mice significantly prevented the increase in serum TG induced by HFD. The in vitro portion of our study showed that fenofibrate upregulated VLDLR transcriptional activity through PPAR response element binding to the VLDLR promoter. The conclusions of our study provide a novel mechanism for the TG-lowering effects of fenofibrate in the treatment of dyslipidemia.