Fibroblast growth factor 21 is induced by endoplasmic reticulum stress.

Increased hepatic expression is held responsible for elevated serum levels of fibroblast growth factor 21 (FGF21) in non-alcoholic fatty liver disease (NAFLD) but the underlying molecular mechanism is unclear. In the present study we tested the postulate that the metabolic hormone FGF21 is regulated by endoplasmic reticulum (ER) stress, a condition that is observed in a number of diseases including NAFLD and results in activation of an adaptive response known as the unfolded protein response (UPR). ER stress stimuli were found to induce expression of Fgf21 mRNA in H4IIE hepatoma cells and in isolated rat hepatocytes. Moreover, intraperitoneal injection of the ER stressor tunicamycin induced hepatic Fgf21 expression in mice and resulted in marked elevation of serum FGF21 levels. The effect of ER stress on FGF21 expression could be mimicked by overexpression of ATF4, a transcriptional effector of the PERK-branch of the UPR. In silico analysis revealed the presence of two binding sites for ATF4 in the FGF21 promoter region. Combined disruption of these elements, abrogated FGF21 promoter activity induced by ER stress or ATF4 overexpression. These findings implicate the PERK/eIF2alpha/ATF4 cascade in ER stress regulation of FGF21. A consequence of this notion is that other intracellular stress signaling pathways that converge at eIF2alpha, can regulate FGF21 expression. Indeed, both nutrient (amino acid deprivation) and oxidative stress (arsenite) were found to induce Fgf21 expression in hepatoma cells and isolated rat hepatocytes. In conclusion, FGF21 expression is regulated by ER stress and additional intracellular stress signaling pathways. Our findings suggest that increased cellular stress in fatty livers may underlie the elevated FGF21 levels observed in patients with NAFLD.

Schaap FG ，Kremer AE ，Lamers WH ，Jansen PL ，Gaemers IC ... -  《-》

Fibroblast growth factor 21 is regulated by the IRE1α-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis.

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.

Jiang S ，Yan C ，Fang QC ，Shao ML ，Zhang YL ，Liu Y ，Deng YP ，Shan B ，Liu JQ ，Li HT ，Yang L ，Zhou J ，Dai Z ，Liu Y ，Jia WP ... -  《-》

Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress.

Kim SH ，Kim KH ，Kim HK ，Kim MJ ，Back SH ，Konishi M ，Itoh N ，Lee MS ... -  《-》

Fibroblast growth factor 21 induction by activating transcription factor 4 is regulated through three amino acid response elements in its promoter region.

Maruyama R ，Shimizu M ，Li J ，Inoue J ，Sato R ... -  《-》

Fibroblast growth factor 21 protects rat cardiomyocytes from endoplasmic reticulum stress by promoting the fibroblast growth factor receptor 1-extracellular signal‑regulated kinase 1/2 signaling pathway.

Liang P ，Zhong L ，Gong L ，Wang J ，Zhu Y ，Liu W ，Yang J ... -  《-》