Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China; State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
J Biol Chem. 2024 Mar;300(3):105661. doi: 10.1016/j.jbc.2024.105661. Epub 2024 Jan 20.
Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), has emerged as a prevalent cause of liver cirrhosis and hepatocellular carcinoma, posing severe public health challenges worldwide. The incidence of NASH is highly correlated with an increased prevalence of obesity, insulin resistance, diabetes, and other metabolic diseases. Currently, no approved drugs specifically targeted for the therapies of NASH partially due to the unclear pathophysiological mechanisms. G protein-coupled estrogen receptor 1 (GPER1) is a membrane estrogen receptor involved in the development of metabolic diseases such as obesity and diabetes. However, the function of GPER1 in NAFLD/NASH progression remains unknown. Here, we show that GPER1 exerts a beneficial role in insulin resistance, hepatic lipid accumulation, oxidative stress, or inflammation in vivo and in vitro. In particular, we observed that the lipid accumulation, inflammatory response, fibrosis, or insulin resistance in mouse NAFLD/NASH models were exacerbated by hepatocyte-specific GPER1 knockout but obviously mitigated by hepatic GPER1 activation in female and male mice. Mechanistically, hepatic GPER1 activates AMP-activated protein kinase signaling by inducing cyclic AMP release, thereby exerting its protective effect. These data suggest that GPER1 may be a promising therapeutic target for NASH.
非酒精性脂肪性肝病（NAFLD），特别是非酒精性脂肪性肝炎（NASH），已成为肝硬化和肝细胞癌的主要病因，在全球范围内对公共健康构成严重挑战。NASH 的发病率与肥胖症、胰岛素抵抗、糖尿病和其他代谢性疾病的患病率增加密切相关。目前，尚无专门针对 NASH 治疗的批准药物，部分原因是其病理生理学机制尚不清楚。G 蛋白偶联雌激素受体 1（GPER1）是一种参与肥胖和糖尿病等代谢性疾病发展的膜雌激素受体。然而，GPER1 在 NAFLD/NASH 进展中的作用仍不清楚。在这里，我们表明 GPER1 在体内和体外的胰岛素抵抗、肝脂质积累、氧化应激或炎症中发挥有益作用。特别是，我们观察到，在雄性和雌性小鼠的 NAFLD/NASH 模型中，肝细胞特异性 GPER1 敲除会加剧脂质积累、炎症反应、纤维化或胰岛素抵抗，但肝 GPER1 激活明显减轻了这些病变。从机制上讲，肝 GPER1 通过诱导环 AMP 释放激活 AMP 激活的蛋白激酶信号通路，从而发挥其保护作用。这些数据表明，GPER1 可能是 NASH 的一个有前途的治疗靶点。
