Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy  

作　　者：Meng-Yuan Jiang Wan-Rong Man Xue-Bin Zhang Xiao-Hua Zhang Yu Duan Jie Lin Yan Zhang Yang Cao De-Xi Wu Xiao-Fei Shu Lei Xin Hao Wang Xiao Zhang Cong-Ye Li Xiao-Ming Gu Xuan Zhang Dong-Dong Sun 

机构地区：[1]Department of Cardiology,Xijing Hospital,Air Force Medical University,Xi’an,710032,China [2]Department of Basic Medicine,Air Force Medical University,Xi’an,710032,China [3]Department of Physiology and Pathophysiology,Air Force Medical University,Xi’an,710032,China [4]Institute for Hospital Management Research,Chinese PLA General Hospital,Beijing,100853,China

出　　处：《Military Medical Research》2024年第5期625-642,共18页军事医学研究（英文版）

基　　金：National Natural Science Foundation of China(82070398,81922008);Key Basic Research Projects of Basic Strengthening Plan(2022-JCJQ-ZD-095-00);Top Young Talents Special Support Program in Shaanxi Province(2020).

摘　　要：Background Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid β-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism.MethodsA high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC–MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator.ResultsThe expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC–MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knock

关 键 词：Diabetic cardiomyopathy Mitochondrial translocation Mitochondrial function Fatty acidβ-oxidation 

分 类 号：R587.2[医药卫生—内分泌] R542.2[医药卫生—内科学]