Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy
作者机构：Department of CardiologyXijing HospitalAir Force Medical UniversityXi’an710032China Department of Basic MedicineAir Force Medical UniversityXi’an710032China Department of Physiology and PathophysiologyAir Force Medical UniversityXi’an710032China Institute for Hospital Management ResearchChinese PLA General HospitalBeijing100853China
出 版 物：《Military Medical Research》 (军事医学研究（英文版）)
年 卷 期：2024年第11卷第5期
页 面：625-642页
核心收录：
学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学]
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)
主 题：Diabetic cardiomyopathy Mitochondrial translocation Mitochondrial function Fatty acidβ-oxidation
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 *** 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 *** 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
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