Estrogen Receptor α Regulates Metabolic-Associated Fatty Liver Disease by Targeting NLRP3–GSDMD Axis-Mediated Hepatocyte Pyroptosis

作者：Xiaona Gao, Shuhui Liu, Lei Tan, Chenchen Ding, Wentao Fan, Zhangshan Gao, Mengcong Li, Zhihui Tang, Yuting Wu, Lei Xu, Liping Yan, Yan Luo, Suquan Song · 发表于：Journal of Agricultural and Food Chemistry · 年份：2021 · DOI：10.1021/acs.jafc.1c05400 · 被引用次数：34 · 研究领域：Inflammasome and immune disorders、Liver Disease Diagnosis and Treatment、Diet, Metabolism, and Disease

Metabolic-associated fatty liver disease (MAFLD) is currently one of the main causes of chronic liver disease, but its potential mechanism remains unclear. This study proved that estrogen receptor α (ERα) could negatively control hepatocyte pyroptosis by inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, gasdermin D (GSDMD)-N generation, propidium iodide (PI) uptake, lactate dehydrogenase (LDH) release, and pro-inflammatory cytokine (IL-1β and IL-18) release. Furthermore, inhibition of pyroptosis ameliorated ERα deletion-induced metabolic dysfunction, insulin resistance, and liver injury. Mechanistically, ERα was confirmed to inhibit pyroptosis by directly interacting with GSDMD, and GSDMD blockade reversed the ERα inhibition-induced pyroptosis and improved lipid accumulation in hepatocytes. Notably, the treatment of wild-type (WT) mice with genistein, a phytoestrogen, could attenuate high-fat diet (HFD)-induced liver lipid steatosis and inhibit NLRP3-GSDMD-mediated pyroptosis. Results provide new insights into the underlying mechanism of pyroptosis regulation and uncover the potential treatment target of MAFLD.