Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and is Activated by PPARβ/δ Deficiency

• Main Authors: Zarei, Mohammad, Barroso, Emma, Leiva, Rosana, Barniol-Xicota, Marta, Pujol, Eugènia, Escolano, Carmen, Vázquez, Santiago, Palomer, Xavier, Pardo, Virginia, González-Rodríguez, Águeda, Valverde, Ángela M., Quesada-López, Tania, Villarroya, Francesc, Wahli, Walter, Vázquez-Carrera, Manuel
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2016
• Subjects: ATF4; ER stress
• Online Access: https://hdl.handle.net/10356/83383; http://hdl.handle.net/10220/41419
• Institution: Nanyang Technological University

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. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in liver of PPARβ/δ-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 2α (eIF2α) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2α 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. Interestingly, increased Fgf21 expression in mice fed a HFD or hepatocytes exposed to palmitate was accompanied by reduced PPARβ/δ 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 and these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.