SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation
Pingping Lai, Guolin Miao, Ying Zhao, Yufei Han, Yanwei Li, Yiran Liu, Jiabao Guo, Wenxi Zhang, Xin Guo, Yitong Xu, Lianxin Zhang, Gonglie Chen, Zihao Zhou, Si Mei, Jingxuan Chen, Jinxuan Chen, Luzheng Xu, Chong Zhang, Yang Ding, Xiaoguang Dou, Shengmei Wen, Sin Man Lam, Guanghou Shui, Yuhui Wang, Wei Huang, Dongyu Zhao, Xunde Xian
Abstract
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. Scavenger receptor class A member 3 (SR-A3) is implicated in metabolic diseases, but its relationship with MAFLD remains unclear. Here, the authors show that SR-A3 is an important modulator of hepatic energy metabolism and is a potential therapeutic target against MAFLD.