Estrogen Receptor α Regulates Metabolic-Associated Fatty Liver Disease by Targeting NLRP3–GSDMD Axis-Mediated Hepatocyte Pyroptosis,Journal of Agricultural and Food Chemistry

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Estrogen Receptor α Regulates Metabolic-Associated Fatty Liver Disease by Targeting NLRP3–GSDMD Axis-Mediated Hepatocyte Pyroptosis
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2021-11-24 , 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

Affiliation

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.

中文翻译：

雌激素受体α通过靶向NLRP3-GSDMD轴介导的肝细胞焦亡调节代谢相关脂肪肝

代谢相关性脂肪肝（MAFLD）是目前慢性肝病的主要原因之一，但其潜在机制尚不清楚。本研究证明雌激素受体α (ERα) 可通过抑制 NOD 样受体家族 pyrin 结构域包含 3 (NLRP3) 炎性体激活、gasdermin D (GSDMD)-N 生成、碘化丙啶 (PI) 摄取、乳酸脱氢酶，对肝细胞焦亡产生负向控制(LDH) 释放和促炎细胞因子（IL-1β 和 IL-18）释放。此外，抑制细胞焦亡可改善 ERα 缺失诱导的代谢功能障碍、胰岛素抵抗和肝损伤。从机制上讲，ERα 被证实通过直接与 GSDMD 相互作用来抑制细胞焦亡，并且 GSDMD 阻断逆转了 ERα 抑制诱导的细胞焦亡并改善了肝细胞中的脂质积累。尤其，用植物雌激素染料木黄酮治疗野生型 (WT) 小鼠可以减轻高脂饮食 (HFD) 诱导的肝脏脂质脂肪变性并抑制 NLRP3-GSDMD 介导的细胞焦亡。结果为细胞焦亡调节的潜在机制提供了新的见解，并揭示了 MAFLD 的潜在治疗目标。

更新日期：2021-12-08

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