title: Fibroblast growth factor 21 is regulated by the IRE1α-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis.
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.
authors.affiliation: From the Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, and Shanghai Key Clinical Center for Metabolic Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai 200233.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yan
authors.affiliation: From the Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, and Shanghai Key Clinical Center for Metabolic Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai 200233.
authors.forename: Qi-chen
authors.initials: QC
authors.lastname: Fang
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and.
authors.forename: Meng-le
authors.initials: ML
authors.lastname: Shao
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and.
authors.forename: Yong-liang
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and.
authors.forename: Yi-ping
authors.initials: YP
authors.lastname: Deng
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and.
authors.forename: Bo
authors.initials: B
authors.lastname: Shan
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and.
authors.forename: Jing-qi
authors.initials: JQ
authors.lastname: Liu
authors.affiliation: From the Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, and Shanghai Key Clinical Center for Metabolic Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai 200233.
authors.forename: Hua-ting
authors.initials: HT
authors.lastname: Li
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: the Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: the Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dai
authors.affiliation: the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, and liuy@sibs.ac.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, and Shanghai Key Clinical Center for Metabolic Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai 200233, wpjia@sjtu.edu.cn.
authors.forename: Wei-ping
authors.initials: WP
authors.lastname: Jia
mesh_terms: D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004722:Endoribonucleases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C528229:ERN1 protein, human; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D004722:Endoribonucleases
keywords: ER Stress; Fibroblast Growth Factor (FGF); Hepatocyte; Liver Metabolism; Unfolded Protein Response (UPR)