| First Author | Zarei M | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 10 | Pages | 3185-99 |
| PubMed ID | 27486236 | Mgi Jnum | J:247176 |
| Mgi Id | MGI:5923163 | Doi | 10.2337/db16-0155 |
| Citation | Zarei M, et al. (2016) Heme-Regulated eIF2alpha Kinase Modulates Hepatic FGF21 and Is Activated by PPARbeta/delta Deficiency. Diabetes 65(10):3185-99 |
| abstractText | Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) beta/delta deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARbeta/delta-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2alpha (eIF2alpha) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2alpha and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARbeta/delta and activation of the HRI-eIF2alpha-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels. |
