Usui Mai, Tsurekawa Yu, Ikehara Tatsuya, Shimazaki Atsuyuki, Vijayakumar Archana, Myers Robert P, Subramanian G Mani, Murakami Eisuke
Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
OrsoBio, Inc., Menlo Park, CA 94025, USA.
J Mol Cell Cardiol Plus. 2025 Jun 2;13:100459. doi: 10.1016/j.jmccpl.2025.100459. eCollection 2025 Sep.
Impaired myocardial energetics, including fatty acid oxidation (FAO), is a hallmark feature in the pathophysiology of various disorders. Deficiency of adipose triglyceride lipase (ATGL) results in impaired FAO which leads to severe heart failure due to massive triglyceride accumulation in cardiac muscle and coronary vasculature. Acetyl-CoA carboxylase 2 (ACC2) is a mitochondrial enzyme that regulates FAO; ACC2 inhibition increases transport of fatty acids into mitochondria for oxidation. In this study, the murine ATGL knockout (KO) model of severe heart failure was used to evaluate the effects ACC2 inhibition induced by whole body genetic KO ( double KO mice) and pharmacological inhibition with TLC-3595, an oral, selective small molecule inhibitor of ACC2. Both genetic deletion of and treatment with TLC-3595 in KO mice promoted mitochondrial FAO, reduced cardiac lipid accumulation and remodeling, and led to significant improvements in cardiac function, locomotor activity, and survival. Metabolite profiling of cardiac tissue of double KO mice and KO mice treated with TLC-3595 revealed ACC2-specific changes, including reduced malonyl-CoA and increased short-, medium-, and long-chain acylcarnitines, consistent with improved FAO. These findings support the therapeutic targeting of ACC2 for the treatment of heart failure associated with impaired FAO.
心肌能量代谢受损，包括脂肪酸氧化（FAO）受损，是各种疾病病理生理学的一个标志性特征。脂肪甘油三酯脂肪酶（ATGL）缺乏会导致FAO受损，进而由于心肌和冠状血管中大量甘油三酯积累而导致严重心力衰竭。乙酰辅酶A羧化酶2（ACC2）是一种调节FAO的线粒体酶；抑制ACC2可增加脂肪酸向线粒体的转运以进行氧化。在本研究中，使用严重心力衰竭的小鼠ATGL基因敲除（KO）模型来评估全身基因敲除（双敲除小鼠）和用ACC2的口服选择性小分子抑制剂TLC-3595进行药物抑制所诱导的ACC2抑制的效果。在KO小鼠中，ACC2的基因缺失和用TLC-3595治疗均促进了线粒体FAO，减少了心脏脂质积累和重塑，并导致心脏功能、运动活性和存活率显著改善。对双敲除小鼠和用TLC-3595治疗的KO小鼠的心脏组织进行代谢物分析，发现了ACC2特异性变化，包括丙二酰辅酶A减少以及短链、中链和长链酰基肉碱增加，这与改善的FAO一致。这些发现支持将ACC2作为治疗与FAO受损相关的心力衰竭的治疗靶点。
