Chronic overnutrition and a sedentary lifestyle promote imbalances in metabolism, often manifesting as risk factors for life-threating diseases such as atherosclerotic cardiovascular disease (ASCVD) and nonalcoholic fatty liver disease (NAFLD). Nucleocytosolic acetyl-coenzyme A (CoA) has emerged as a central signaling node used to coordinate metabolic adaptations in response to a changing nutritional status. ATP-citrate lyase (ACL) is the enzyme primarily responsible for the production of extramitochondrial acetyl-CoA and is thus strategically positioned at the intersection of nutrient catabolism and lipid biosynthesis. Here, we discuss recent findings from preclinical studies, as well as Mendelian and clinical randomized trials, demonstrating the importance of ACL activity in metabolism, and supporting its inhibition as a potential therapeutic approach to treating ASCVD, NAFLD, and other metabolic disorders.

慢性营养不良和久坐不动的生活方式会促进新陈代谢的失衡，经常表现为威胁生命的疾病的危险因素，例如动脉粥样硬化性心血管疾病（ASCVD）和非酒精性脂肪肝疾病（NAFLD）。核细胞质乙酰辅酶A（CoA）已成为一个中心信号节点，可用于响应营养状况的变化来协调代谢适应。ATP柠檬酸裂解酶（ACL）是主要负责线粒体乙酰辅酶A产生的酶，因此在战略上位于营养物质分解代谢和脂质生物合成的交叉点。在这里，我们讨论了临床前研究以及孟德尔和临床随机试验的最新发现，证明了ACL活性在新陈代谢中的重要性，