Heme-regulated eIF2α kinase modulates hepatic FGF21 and is activated by PPARβ/δ 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) b/d deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARb/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 PPARb/d and activation of the HRI-eIF2α-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.This study was partly supported by funds from the Spanish Ministry of the Economy and Competitiveness (SAF2015-65267-R to Á.M.V., SAF2014-55725 to F.V., and SAF2012-30708 and SAF2015-64146-R to M.V.-C.) and the European Union European Regional Development Fund. CIBERDEM and CIBEROBN are Instituto de Salud Carlos III Health Institute projects. T.Q.-L. is supported by a CONACyT (National Council for Science and Technology in Mexico) PhD scholarship. W.W. is supported by start-up grants from the Lee Kong Chian School of Medicine, Nanyang Technological University, and by the Région Midi-Pyrénées, France.Peer Reviewe