title: ATF4- and CHOP-dependent induction of FGF21 through endoplasmic reticulum stress.
abstract: Fibroblast growth factor 21 (FGF21) is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER) stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD). In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (CHOP). Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP-/- mouse primary hepatocytes (MPH), and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively.
authors.affiliation: College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
authors.forename: Xiao-shan
authors.initials: XS
authors.lastname: Wan
authors.affiliation: Translation Medicine Research Center, Lishui People's Hospital, Wenzhou Medical University, Lishui, Zhejiang 323000, China.
authors.forename: Xiang-hong
authors.initials: XH
authors.lastname: Lu
authors.affiliation: Molecular Pharmacology Research Center, Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Ye-cheng
authors.initials: YC
authors.lastname: Xiao
authors.affiliation: Department of Ophthalmology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361000, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 323000, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Translation Medicine Research Center, Lishui People's Hospital, Wenzhou Medical University, Lishui, Zhejiang 323000, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Ding
authors.affiliation: Molecular Pharmacology Research Center, Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Molecular Pharmacology Research Center, Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 323000, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Pharmacology Research Center, Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Yan-Long
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Molecular Pharmacology Research Center, Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Zhu-mei
authors.initials: ZM
authors.lastname: Xu
authors.affiliation: Translation Medicine Research Center, Lishui People's Hospital, Wenzhou Medical University, Lishui, Zhejiang 323000, China ; Molecular Pharmacology Research Center, Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.affiliation: College of Basic Medical Sciences, Jilin University, Changchun 130021, China ; Molecular Pharmacology Research Center, Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Xiao-kun
authors.initials: XK
authors.lastname: Li
mesh_terms: D016475:3T3 Cells; D051701:Activating Transcription Factor 4 / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005346:Fibroblast Growth Factors / Q000235:genetics*; D006207:Half-Life; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: C081452:Atf4 protein, mouse; C497250:Ddit3 protein, mouse; C414620:fibroblast growth factor 21; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D005346:Fibroblast Growth Factors