Estrogen Receptor a Regulates Metabolic-Associated Fatty Liver Disease by Targeting NLRP3-GSDMD Axis-Mediated Hepatocyte Pyroptosis
Estrogen Receptor a Regulates Metabolic-Associated Fatty Liver Disease by Targeting NLRP3-GSDMD Axis-Mediated Hepatocyte Pyroptosis
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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性肝病
DOI：
10.1021/acs.jafc.1c05400
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发表时间：
2021-12-08
影响因子：
6.1
通讯作者：
Song, Suquan
中科院分区：
文献类型：
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作者：
Gao, Xiaona;Liu, Shuhui;Song, Suquan
代谢相关脂肪性肝病（MAFLD）是目前慢性肝病的主要原因之一，但其潜在机制仍不清楚。这项研究证明，雌激素受体α（ERα）可以通过抑制NOD样受体家族pyrin结构域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（LDH）释放和促炎细胞因子（IL-1β和IL-18）释放来负向控制肝细胞焦亡。此外，抑制细胞焦亡可改善 ER α 缺失引起的代谢功能障碍、胰岛素抵抗和肝损伤。从机制上讲，ER α 被证实可通过直接与 GSDMD 相互作用来抑制细胞焦亡，而 GSDMD 阻断可逆转 ER α 抑制诱导的细胞焦亡并改善肝细胞中的脂质积累。值得注意的是，用金雀异黄素（一种植物雌激素）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 的潜在治疗靶点。
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 alpha (ER alpha) 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-1 beta and IL-18) release. Furthermore, inhibition of pyroptosis ameliorated ER alpha deletion-induced metabolic dysfunction, insulin resistance, and liver injury. Mechanistically, ER alpha was confirmed to inhibit pyroptosis by directly interacting with GSDMD, and GSDMD blockade reversed the ER alpha 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.