Hepatic regulation of VLDL receptor by PPAR beta/delta and FGF21 modulates non-alcoholic fatty liver disease

Objective: The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Methods: Studies were conducted in wild-type and Ppar beta/delta-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis. Results: Increased VLDLR levels were observed in liver of Ppar beta/delta-null mice and in Ppar beta/delta-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2 alpha (e1F2 alpha) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPAR beta/delta mRNA abundance and DNA-binding activity compared with control subjects. Conclusions: Overall, these findings provide new mechanisms by which PPAR beta/delta and FGF21 regulate VLDLR levels and influence hepatic steatosis development. 2017 The Authors. Published by Elsevier GmbH.