Estrogen receptor α mediated M1/M2 macrophages polarization plays a critical role in NASH of female mice

• Published in: Biochemical and biophysical research communications 2022-03, Vol.596, p.63-70
• Main Authors: Shu, Zhiping, Zhang, Guopeng, Zhu, Xiaohua, Xiong, Wenqian
• Format: Article
• Language: English
• Subjects: Animals; CCR2; Cells, Cultured; Cytokines - genetics; Cytokines - metabolism; Diet, High-Fat - adverse effects; ERα; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogens - pharmacology; Female; Gene Expression Regulation - drug effects; Humans; M1 macrophages; Macrophage Activation - drug effects; Macrophage Activation - genetics; Macrophages - classification; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Nonalcoholic steatohepatitis; Ovariectomy; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Receptors, CCR2 - genetics; Receptors, CCR2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transcriptional regulation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.01.085

Owing to lacking protective effect of estrogen, OVX mice have higher risk of non-alcoholic fatty liver disease compared with normal female mice, when fed with high fat diet. Our study was to explore how estrogen protect against nonalcoholic steatohepatitis in female mice. We found that, lacking estrogen, M1 macrphages was activated and promoted steatohepatitis in obese OVX mice. And, ERα was responsible for estrogen to inhibit M1 macrphages activation and steatohepatitis. ERα knockdown aggravated M1 macrophages infiltration by transcriptionally upregulated its CCR2 expression. CCR2 antagonist effectively improved nonalcoholic steatohepatitis, ER stress and insulin resistance in ERα knockdown obese female mice. These results demonstrated ERα mediated M1 macrophages activation played a key role in nonalcoholic steatohepatitis. •Estrogen deficiency induced macrophages recruitment and nonalcoholic steatohepatitis in OVX mice.•ERα knockdown accelerated hepatic steatosis, M1 macrophage infiltration and fibrogenesis in obese female mice.•Estrogen promoted ERα to bind to CCR2 promoter and inhibited its transcriptional activity and expression.•CCR2 antagonist attenuated M1 macrophages activation and nonalcoholic steatohepatitis in obese ERα knockdown mice.