Fibroblast Growth Factor 21 Is Regulated by the IRE1α-XBP1 Branch of the Unfolded Protein Response and Counteracts Endoplasmic Reticulum Stress-induced Hepatic Steatosis

Shan Jiang,Cheng Yan,Qi-Chen Fang,Meng-Le Shao,Yong-Liang Zhang,Yang Liu,Yi-Ping Deng,Bo Shan,Jing-Qi Liu,Hua-Ting Li,Liu Yang,Jian Zhou,Zhi Dai,Yong Liu,Wei-Ping Jia

doi:10.1074/jbc.m114.565960

Abstract

Endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR) and represents a critical mechanism that underlies metabolic dysfunctions. Fibroblast growth factor 21 (FGF21), a hormone that is predominantly secreted by the liver, exerts a broad range of effects upon the metabolism of carbohydrates and lipids. Although increased circulating levels of FGF21 have been documented in animal models and human subjects with obesity and nonalcoholic fatty liver disease, the functional interconnections between metabolic ER stress and FGF21 are incompletely understood. Here, we report that increased ER stress along with the simultaneous elevation of FGF21 expression were associated with the occurrence of nonalcoholic fatty liver disease both in diet-induced obese mice and human patients. Intraperitoneal administration of the ER stressor tunicamycin in mice resulted in hepatic steatosis, accompanied by activation of the three canonical UPR branches and increased the expression of FGF21. Furthermore, the IRE1α-XBP1 pathway of the UPR could directly activate the transcriptional expression of Fgf21. Administration of recombinant FGF21 in mice alleviated tunicamycin-induced liver steatosis, in parallel with reduced eIF2α-ATF4-CHOP signaling. Taken together, these results suggest that FGF21 is an integral physiological component of the cellular UPR program, which exerts beneficial feedback effects upon lipid metabolism through counteracting ER stress.

Highlights

Both are involved in metabolic homeostasis, the interconnection between Endoplasmic reticulum (ER) stress and Fibroblast growth factor 21 (FGF21) remains incompletely understood
We found that hepatic FGF21 is transcriptionally up-regulated by the inositol-requiring enzyme 1 (IRE1)␣-X-box-binding protein 1 (XBP1) pathway of the unfolded protein response (UPR), which can in turn suppress the eIF2␣-ATF4-C/EBP homologous protein (CHOP) pathway in hepatocytes, alleviating ER stress-induced hepatic steatosis
Immunoblotting analyses showed that FGF21 protein levels were increased in livers of high fat diet (HFD)-fed obese mice, which were accompanied by increased phosphorylation of IRE1␣ and eIF2␣ (Fig. 1C), along with increased nuclear accumulation of XBP1s, ATF4, and activating transcription factor 6 (ATF6) proteins (Fig. 1D)

Summary

Introduction

Both are involved in metabolic homeostasis, the interconnection between ER stress and FGF21 remains incompletely understood. Results: Directly up-regulated by the IRE1␣-XBP1 pathway, FGF21 could alleviate ER stress-induced liver steatosis. Increased circulating levels of FGF21 have been documented in animal models and human subjects with obesity and nonalcoholic fatty liver disease, the functional interconnections between metabolic ER stress and FGF21 are incompletely understood. We report that increased ER stress along with the simultaneous elevation of FGF21 expression were associated with the occurrence of nonalcoholic fatty liver disease both in diet-induced obese mice and human patients. Intraperitoneal administration of the ER stressor tunicamycin in mice resulted in hepatic steatosis, accompanied by activation of the three canonical UPR branches and increased the expression of FGF21. The IRE1␣-XBP1 pathway of the UPR could directly activate the transcriptional expression of Fgf. Administration of recombinant FGF21 in mice alleviated tunicamycin-induced liver stea-

Methods

Results

Conclusion