清道夫受体A3通过抑制X连锁凋亡抑制蛋白介导的磷酸酶和张力蛋白同源物降解来抑制AKT激活，从而预防非酒精性脂肪性肝炎。
SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation.
作者信息
Lai Pingping, Miao Guolin, Zhao Yinqi, Han Yufei, Li Yanwei, Liu Yiran, Guo Jiabao, Zhang Wenxi, Guo Xin, Xu Yitong, Zhang Lianxin, Chen Gonglie, Zhou Zihao, Mei Si, Chen Jingxuan, Chen Jinxuan, Xu Luzheng, Zhang Chong, Ding Yang, Dou Xiaoguang, Wen Shengmei, Lam Sin Man, Shui Guanghou, Wang Yuhui, Huang Wei, Zhao Dongyu, Xian Xunde
机构信息
Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing, China.
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
出版信息
Nat Commun. 2025 Mar 11;16(1):2430. doi: 10.1038/s41467-025-57585-0.
Scavenger receptor class A member 3 (SR-A3) is implicated in metabolic diseases; however, the relationship between SR-A3 and metabolic dysfunction-associated fatty liver disease (MAFLD) has not been documented. Here, we show that hepatic SR-A3 expression is significantly reduced in human and animal models in the context of MAFLD. Genetic inhibition of SR-A3 in hamsters elicits hyperlipidemia, hyperglycemia, insulin resistance, and hepatic steatosis under chow-diet condition, yet escalates in diet-induced MAFLD. Mechanistically, SR-A3 ablation enhances E3 ligase XIAP-mediated proteasomal ubiquitination of PTEN, leading to AKT hyperactivation. By contrast, hepatic overexpression of human SR-A3 is sufficient to attenuate metabolic disorders in WT hamsters fed a high-fat-high-cholesterol diet and ob/ob mice via suppressing the XIAP/PTEN/AKT axis. In parallel, pharmacological intervention by PTEN agonist oroxin B or lipid lowering agent ezetimibe differentially corrects MAFLD in hamsters.
清道夫受体A类成员3（SR-A3）与代谢性疾病有关；然而，SR-A3与代谢功能障碍相关脂肪性肝病（MAFLD）之间的关系尚未见报道。在此，我们表明在MAFLD背景下，人和动物模型中肝脏SR-A3表达显著降低。在仓鼠中对SR-A3进行基因抑制，在正常饮食条件下会引发高脂血症、高血糖、胰岛素抵抗和肝脂肪变性，但在饮食诱导的MAFLD中会加剧。机制上，SR-A3缺失增强了E3连接酶XIAP介导的PTEN蛋白酶体泛素化，导致AKT过度激活。相比之下，人SR-A3的肝脏过表达足以通过抑制XIAP/PTEN/AKT轴减轻高脂高胆固醇饮食喂养的野生型仓鼠和ob/ob小鼠的代谢紊乱。同时，PTEN激动剂奥罗欣B或降脂药物依折麦布的药物干预可不同程度地纠正仓鼠的MAFLD。
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