Heme-regulated eIF2a kinase modulates hepatic FGF21 and is activated by PPARß/d deficiency
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) ß/d deficiency in hepatic FGF21 regulation. Increa...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Status: | Published version |
| Publication date: | 2016 |
| Country: | España |
| Institution: | Fundació Sant Joan de Déu |
| Repository: | r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu |
| OAI Identifier: | oai:fsjd.fundanetsuite.com:p9987 |
| Online Access: | https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=9987 https://www.scopus.com/inward/record.uri?eid=2-s2.0-84989172272&doi=10.2337%2fdb16-0155&partnerID=40&md5=82b33cf51681ba8d9de7ec9a84235473 |
| Access Level: | Open access |
| Summary: | 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) ß/d deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARß/d-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 2a (eIF2a) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2a 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 PPARß/d and activation of the HRI-eIF2a-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. |
|---|