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

ABSTRACT: 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.

SUBMITTER: Hong T

PROVIDER: S-EPMC6605699 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Hong Ting T Ge Zhijuan Z Zhang Bingjie B Meng Ran R Zhu Dalong D Bi Yan Y

International journal of molecular medicine 20190528 2

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 ...[more]

PMID: 31173165

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Project description:The hepatocyte-derived hormone fibroblast growth factor 21 (FGF21) is a hormone-like regulator of metabolism. The nicotinamide adenine dinucleotide-dependent deacetylase SIRT1 regulates fatty acid metabolism through multiple nutrient sensors. Hepatic overexpression of SIRT1 reduces steatosis and glucose intolerance in obese mice. We investigated mechanisms by which SIRT1 controls hepatic steatosis in mice.Liver-specific SIRT1 knockout (SIRT1 LKO) mice and their wild-type littermates (controls) were divided into groups that were placed on a normal chow diet, fasted for 24 hours, or fasted for 24 hours and then fed for 6 hours. Liver tissues were collected and analyzed by histologic examination, gene expression profiling, and real-time polymerase chain reaction assays. Human HepG2 cells were incubated with pharmacologic activators of SIRT1 (resveratrol or SRT1720) and mitochondrion oxidation consumption rate and immunoblot analyses were performed. FGF21 was overexpressed in SIRT1 LKO mice using an adenoviral vector. Energy expenditure was assessed by indirect calorimetry.Prolonged fasting induced lipid deposition in livers of control mice, but severe hepatic steatosis in SIRT1 LKO mice. Gene expression analysis showed that fasting up-regulated FGF21 in livers of control mice but not in SIRT1 LKO mice. Decreased hepatic and circulating levels of FGF21 in fasted SIRT1 LKO mice were associated with reduced hepatic expression of genes involved in fatty acid oxidation and ketogenesis, and increased expression of genes that control lipogenesis, compared with fasted control mice. Resveratrol or SRT1720 each increased the transcriptional activity of the FGF21 promoter (-2070/+117) and levels of FGF21 messenger RNA and protein in HepG2 cells. Surprisingly, SIRT1 LKO mice developed late-onset obesity with impaired whole-body energy expenditure. Hepatic overexpression of FGF21 in SIRT1 LKO mice increased the expression of genes that regulate fatty acid oxidation, decreased fasting-induced steatosis, reduced obesity, increased energy expenditure, and promoted browning of white adipose tissue.SIRT1-mediated activation of FGF21 prevents liver steatosis caused by fasting. This hepatocyte-derived endocrine signaling appears to regulate expression of genes that control a brown fat-like program in white adipose tissue, energy expenditure, and adiposity. Strategies to activate SIRT1 or FGF21 could be used to treat fatty liver disease and obesity.

Dataset Information

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

Publications

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

Similar Datasets

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