| First Author | Zarei M | Year | 2018 |
| Journal | Mol Metab | Volume | 8 |
| Pages | 117-131 | PubMed ID | 29289645 |
| Mgi Jnum | J:264988 | Mgi Id | MGI:6198995 |
| Doi | 10.1016/j.molmet.2017.12.008 | Citation | Zarei M, et al. (2018) Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease. Mol Metab 8:117-131 |
| abstractText | 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 Pparbeta/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 Pparbeta/delta-null mice and in Pparbeta/delta-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2alpha (eIF2alpha) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-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 PPARbeta/delta mRNA abundance and DNA-binding activity compared with control subjects. CONCLUSIONS: Overall, these findings provide new mechanisms by which PPARbeta/delta and FGF21 regulate VLDLR levels and influence hepatic steatosis development. |
