Wang Lulu, Hu Tingting, Zhang Ruxuan, Shi Yingzhou, Wang Yan, Xuan Qiuhui, Zhou Xinli
Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China; Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, 250012, Jinan, China.
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China; Shandong Institute of Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
Biochem Biophys Res Commun. 2025 Apr 5;756:151583. doi: 10.1016/j.bbrc.2025.151583. Epub 2025 Mar 4.
Obesity, a significant risk factor for cardiovascular diseases, induces cardiolipin (CL) remodeling. Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1), a key enzyme in CL metabolism, drives mitochondrial impairment and cardiac dysfunction in obesity. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) exhibit cardioprotective properties, their effects on ALCAT1-mediated CL remodeling in obesity-induced myocardial injury remain unclear. Male C57BL/6 mice fed a high-fat diet (HFD) or standard diet (STD) for 12 weeks received liraglutide (200 μg/kg/day) or saline during the last 4 weeks. Cardiac function was evaluated by echocardiography; CL content was quantified using LC-MS, and myocardial alterations were assessed through histological and protein analyses. In HFD-fed mice, cardiac lipid accumulation, left ventricular hypertrophy, and myocardial collagen deposition were observed. Additionally, these mice exhibited reduced CL content, altered CL aliphatic chain composition, and upregulated ALCAT1 expression. In contrast, liraglutide treatment significantly increased total CL content, modified CL acyl chain composition, and downregulated ALCAT1 expression. Mechanistically, liraglutide activated the PI3K/AKT pathway via GLP-1 receptor signaling, attenuated oxidative stress markers (3-nitrotyrosine, Rac1 activation), and improved mitochondrial dynamics by reducing DRP1-mediated fission. These results demonstrate that liraglutide mitigates obesity-induced cardiac dysfunction by suppressing ALCAT1-driven CL remodeling, enhancing mitochondrial homeostasis, and reducing oxidative stress. This study elucidates the cardioprotective mechanisms of liraglutide and highlights its therapeutic potential for obesity-related cardiomyopathy.
肥胖是心血管疾病的一个重要风险因素，可诱导心磷脂（CL）重塑。酰基辅酶A：溶血心磷脂酰基转移酶-1（ALCAT1）是CL代谢中的关键酶，在肥胖中会导致线粒体损伤和心脏功能障碍。尽管胰高血糖素样肽-1受体激动剂（GLP-1RAs）具有心脏保护作用，但其对肥胖诱导的心肌损伤中ALCAT1介导的CL重塑的影响仍不清楚。雄性C57BL/6小鼠喂食高脂饮食（HFD）或标准饮食（STD）12周，在最后4周接受利拉鲁肽（200μg/kg/天）或生理盐水。通过超声心动图评估心脏功能；使用液相色谱-质谱法定量CL含量，并通过组织学和蛋白质分析评估心肌变化。在喂食HFD的小鼠中，观察到心脏脂质蓄积、左心室肥厚和心肌胶原沉积。此外，这些小鼠的CL含量降低，CL脂肪链组成改变，ALCAT1表达上调。相比之下，利拉鲁肽治疗显著增加了总CL含量，改变了CL酰基链组成，并下调了ALCAT1表达。机制上，利拉鲁肽通过GLP-1受体信号激活PI3K/AKT途径，减弱氧化应激标志物（3-硝基酪氨酸、Rac1激活），并通过减少DRP1介导的裂变改善线粒体动力学。这些结果表明，利拉鲁肽通过抑制ALCAT1驱动的CL重塑、增强线粒体稳态和减少氧化应激来减轻肥胖诱导的心脏功能障碍。本研究阐明了利拉鲁肽的心脏保护机制，并突出了其对肥胖相关心肌病的治疗潜力。
