Targeting ATP-Citrate Lyase in Hyperlipidemia and Metabolic Disorders

摘要

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. Trends ACL is a cytosolic enzyme dysregulated in many metabolic disorders that catalyzes the production of acetyl-CoA from citrate; it is positioned at the intersection of oxidative phosphorylation and the synthesis of cholesterol and fatty acids. For many years, ACL has been considered a viable target to treat dyslipidemia, but recent insight into its role in lipid and energy metabolism provides additional rationale for its potential utility to address modern challenges in cardiovascular and metabolic health. ACL-dependent protein acetylation has also emerged as an important signal to coordinate lipid metabolism and gene expression with nutritional status. ACL suppression reduces atherogenic lipoproteins, hepatic fat, and inflammation; attenuates experimental atherosclerosis; and improves dysglycemia in multiple disease models. Mendelian randomization studies, used to genetically validate new drug targets, have recently shown that LDL-C lowering mediated by SNPs in the ACLY gene region are associated with reduced ASCVD risk. Late-stage clinical trials demonstrate that the novel ACL inhibitor, bempedoic acid, reduces elevated levels of LDL-cholesterol, and promotes beneficial effects on other metabolic risk factors associated with ASCVD and NAFLD.