SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation
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.
Authors
- Wei Huang (ORCID: https://orcid.org/0000-0002-8284-2310)
- Sin Man Lam (ORCID: https://orcid.org/0000-0001-9037-904X)
- Guolin Miao
- Xunde Xian (ORCID: https://orcid.org/0000-0003-3059-1254)
- Pingping Lai
- Lianxin Zhang (ORCID: https://orcid.org/0000-0002-5076-9518)
- Gonglie Chen (ORCID: https://orcid.org/0000-0002-0402-3141)
- Yitong Xu (ORCID: https://orcid.org/0000-0001-8392-8610)
- Ying Zhao (ORCID: https://orcid.org/0000-0001-7057-1384)
- Jingxuan Chen (ORCID: https://orcid.org/0000-0001-5931-0239)
- Xiaoguang Dou (ORCID: https://orcid.org/0000-0003-1856-7331)
- Jinxuan Chen (ORCID: https://orcid.org/0000-0002-3099-7097)
- Si Mei (ORCID: https://orcid.org/0000-0002-4263-1121)
- Xin Wen Guo (ORCID: https://orcid.org/0000-0003-4995-8378)
- Shengmei Wen (ORCID: https://orcid.org/0009-0005-1912-9757)
- Dongyu Zhao (ORCID: https://orcid.org/0000-0003-2344-5718)
- Guanghou Shui (ORCID: https://orcid.org/0000-0002-1621-9643)
- Yuhui Wang (ORCID: https://orcid.org/0000-0003-2936-3377)
- Chong Zhang (ORCID: https://orcid.org/0000-0002-8113-5585)
- Jiabao Guo
- Yang Ding (ORCID: https://orcid.org/0000-0001-8211-9563)
- Yiran Liu (ORCID: https://orcid.org/0000-0002-9935-7768)
- Luzheng Xu
- Wenxi Zhang (ORCID: https://orcid.org/0009-0003-2775-6473)
- Zihao Zhou (ORCID: https://orcid.org/0000-0002-6296-3473)
- Yufei Han
- Yanwei Li (ORCID: https://orcid.org/0009-0008-3939-6360)
Institutions
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- LipidALL Technologies (China) (CN)
- Institute of Genetics and Developmental Biology (CN)
- Peking University Third Hospital (CN)
- China Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1038/s41467-025-57585-0
- Citations
- 3
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 4.06