2. Academic Validation
  3. Estrogen Receptor α Regulates Metabolic-Associated Fatty Liver Disease by Targeting NLRP3-GSDMD Axis-Mediated Hepatocyte Pyroptosis

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

  • J Agric Food Chem. 2021 Dec 8;69(48):14544-14556. doi: 10.1021/acs.jafc.1c05400.
Xiaona Gao 1 2,  Shuhui Liu 1,  Lei Tan 3,  Chenchen Ding 1,  Wentao Fan 1,  Zhangshan Gao 1,  Mengcong Li 1,  Zhihui Tang 1,  Yuting Wu 1,  Lei Xu 4,  Liping Yan 1,  Yan Luo 3,  Suquan Song 1
Affiliations

Affiliations

  • 1 MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu 210095, People's Republic of China.
  • 2 Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi 330000, People's Republic of China.
  • 3 Administration for Market Regulation of Guangdong Province Key Laboratory of Supervision for Edible Agricultural Products, Shenzhen Centre of Inspection and Testing for Agricultural Products, Shenzhen, Guangdong 518000, People's Republic of China.
  • 4 Fujian Agricultural Vocational Technical College, Fuzhou, Fujian 350119, People's Republic of China.
PMID: 34817168 DOI: 10.1021/acs.jafc.1c05400
Abstract

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.

Keywords

ERα; GSDMD; MAFLD; NLRP3 inflammasome; pyroptosis.

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