ATF4- and CHOP-Dependent Induction of FGF21 through Endoplasmic Reticulum Stress

• Published in: BioMed research international Vol. 2014; no. 2014; pp. 1 - 9
• Main Authors: Lu, Xiang-hong, Wan, Xiao-shan, Xiao, Ye-cheng, Lin, Yuan, Zhu, Hong, Ding, Ting, Yang, Ying, Huang, Yan, Zhang, Yi, Liu, Yan-Long, Xu, Zhu-mei, Xiao, Jian, Li, Xiao-kun
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Puplishing Corporation 01.01.2014; Hindawi Publishing Corporation; John Wiley & Sons, Inc
• Subjects: 3T3 Cells; Activating Transcription Factor 4 - genetics; Amino acids; Animals; Binding sites; Cell Line; Diabetes; Disease; Endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum Stress - genetics; Fibroblast growth factors; Fibroblast Growth Factors - genetics; Gene expression; Half-Life; Health aspects; Homeostasis; Hospitals; Insulin; Insulin resistance; Kinases; Male; Metabolic disorders; Mice; Mice, Inbred C57BL; Physiological aspects; Promoter Regions, Genetic - genetics; Protein Binding - genetics; Proteins; Rodents; Science; Signal Transduction - genetics; Stress (Physiology); Studies; Traditional Chinese medicine; Transcription Factor CHOP - genetics; Transcription, Genetic - genetics; Transcriptional Activation - genetics
• DOI: 10.1155/2014/807874
• ISSN: 2314-6133; 2314-6141

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.