Murine double minute 2 aggravates adipose tissue dysfunction through ubiquitin-mediated six-transmembrane epithelial antigen of prostate 4 degradation

Wei Zhao; Qiang Xu; Jiahui Yang; Xianghong Xie; Chunmei Li; Weihong Zhang; Enhui Chen; Yanfang Guo; Mingyue Gao; Jie Shi; Huabing Zhang; Hong Yao; Meixia Li; Li Yan; Fude Fang; Wenming Wu; Xiaojun Liu

doi:10.1016/j.isci.2022.104544

Murine double minute 2 aggravates adipose tissue dysfunction through ubiquitin-mediated six-transmembrane epithelial antigen of prostate 4 degradation

iScience. 2022 Jun 7;25(7):104544. doi: 10.1016/j.isci.2022.104544. eCollection 2022 Jul 15.

Authors

Wei Zhao¹, Qiang Xu², Jiahui Yang³, Xianghong Xie¹, Chunmei Li¹, Weihong Zhang³, Enhui Chen⁴, Yanfang Guo¹, Mingyue Gao¹, Jie Shi⁵, Huabing Zhang⁶, Hong Yao³, Meixia Li⁷, Li Yan⁴, Fude Fang¹, Wenming Wu⁸, Xiaojun Liu¹

Affiliations

¹ State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
² Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China.
³ Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China.
⁴ Department of Pathophysiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
⁵ Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
⁶ Department of Biochemistry and Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei 230032, China.
⁷ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁸ Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China.

Abstract

Healthy adipose tissue is crucial to maintain normal energy homeostasis. Little is known about the role of murine double minute 2 (MDM2), an E3 ubiquitin ligase and has been highlighted in oncopathology, in adipose tissue. Our results indicated that MDM2 expression was associated with nutritional status. Mdm2 adipocyte-specific knock-in (Mdm2-AKI) mice exhibited exacerbated weight gain, insulin resistance, and decreased energy expenditure. Meanwhile, chronic high-fat diet (HFD) exposure caused obvious epididymal white adipose tissue (eWAT) dysfunction, such as senescence, apoptosis, and chronic inflammation, thereby leading to hepatic steatosis in Mdm2-AKI mice. Mechanically, MDM2 could interact with six-transmembrane epithelial antigen of prostate 4 (STEAP4) and inhibit STEAP4 expression through ubiquitin-mediated STEAP4 degradation. Thereinto, the K18 and K161 sites of STEAP4 were ubiquitin-modificated by MDM2. Finally, STEAP4 restoration in eWAT of Mdm2-AKI mice on a HFD rescued MDM2-induced adipose dysfunction, insulin resistance, and hepatic steatosis. Summary, the MDM2-STEAP4 axis in eWAT plays an important role in maintaining healthy adipose tissue function and improving hepatic steatosis.

Keywords: Biological sciences; Immunology; Molecular biology; Proteomics.