Qu Hua, Liu Xiufei, Zhu Jiaran, He Niexia, He Qingshan, Zhang Linlin, Wang Yuren, Gong Xiaoli, Xiong Xin, Liu Jinbo, Wang Chuan, Yang Gangyi, Yang Qingwu, Luo Gang, Zhu Zhiming, Zheng Yi, Zheng Hongting
Department of Endocrinology, Translational Research of Diabetes Key Laboratory of Chongqing Education Commission of China, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
Department of Ultrasound, The Second Affiliated Hospital of Army Medical University, Chongqing, China.
iScience. 2024 May 11;27(6):109796. doi: 10.1016/j.isci.2024.109796. eCollection 2024 Jun 21.
Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.
肥胖和糖尿病等代谢性疾病会引发脂毒性心肌病，其特征为心肌脂质蓄积、功能障碍、肥大、纤维化以及线粒体功能障碍。在此，我们发现线粒体甘油-3-磷酸脱氢酶（mGPDH）是脂毒性心肌病背景下心脏脂肪酸代谢和功能的关键调节因子。心肌细胞特异性缺失mGPDH会加剧高脂饮食诱导的心脏功能障碍、病理性肥大、心肌纤维化以及脂质蓄积。从机制上来说，mGPDH缺乏会抑制去琥珀酰化酶SIRT5的表达，进而使脂肪酸氧化（FAO）循环中的大多数酶发生超琥珀酰化，并促进这些酶的降解。此外，调控SIRT5可消除mGPDH缺失或过表达对心脏功能的影响。最后，在饮食诱导和基因肥胖小鼠模型中，恢复mGPDH均可改善脂质蓄积和心肌病。因此，我们的研究表明，针对mGPDH可能是肥胖和糖尿病背景下脂毒性心肌病的一种有前景的策略。
