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.
Highlights
The fibroblast growth factor family contains 22 members with a wide range of biological functions relevant to regulating cell growth, differentiation, wound healing, development, and angiogenesis [1,2,3]
It has been reported that serum Fibroblast growth factor 21 (FGF21) and hepatic mRNA expression levels in patients with nonalcoholic fatty liver disease (NAFLD) are significantly higher than levels in control subjects, which correlates with a substantial increase in liver triglyceride levels [14,15,16]
FGF21 acts as a hormone-like cytokine on multiple tissues to coordinate carbohydrate and lipid metabolism [4]
Summary
The fibroblast growth factor family contains 22 members with a wide range of biological functions relevant to regulating cell growth, differentiation, wound healing, development, and angiogenesis [1,2,3]. FGF21 has a protective effect on the preservation of pancreatic β-cell function and promotes hepatic and peripheral insulin sensitivity via the prevention of lipolysis, which improves insulin resistance [8,9,10]. FGF21 is expressed predominantly in liver and, to a lower extent, in white adipose tissue, thymus, skeletal muscle, and pancreatic β-cells [4, 9, 13]. It has been reported that serum FGF21 and hepatic mRNA expression levels in patients with NAFLD are significantly higher than levels in control subjects, which correlates with a substantial increase in liver triglyceride levels [14,15,16].
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