Erythropoietin suppresses hepatic steatosis and obesity by inhibiting endoplasmic reticulum stress and upregulating fibroblast growth factor 21

Erythropoietin (EPO), known primarily for its role in erythropoiesis, was recently reported to play a beneficial role in regulating lipid metabolism; however, the underlying mechanism through which EPO decreases hepatic lipid accumulation requires further investigation. Endoplasmic reticulum (ER) stress may contribute to the progression of hepatic steatosis. The present study investigated the effects of EPO on regulating ER stress in fatty liver. It was demonstrated that EPO inhibited hepatic ER stress and steatosis in vivo and in vitro. Interestingly, these beneficial effects were abrogated in liver-specific sirtuin 1 (SIRT1)-knockout mice compared with wild-type littermates. In addition, in palmitate-treated hepatocytes, small interfering RNA-mediated SIRT1 silencing suppressed the effects of EPO on lipid-induced ER stress. Additionally, EPO stimulated hepatic fibroblast growth factor 21 (FGF21) expression and secretion in a SIRT1-dependent manner in mice. Furthermore, the sensitivity of hepatocytes from obese mice to FGF21 was restored following treatment with EPO. Collectively, the results of the present study revealed a new mechanism underlying the regulation of hepatic ER stress and FGF21 expression induced by EPO; thus, EPO may be considered as a potential therapeutic agent for the treatment of fatty liver and obesity.

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