title: ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia.
abstract: OBJECTIVE
  ATP-citrate lyase (ACLY) has re-emerged as a drug target for LDL cholesterol (LDL-C) lowering. We review ACLY as a therapeutic strategy, its genetics, its molecular and cellular biology, and also its inhibition.
  
  
  RESULTS
  ACLY is a critical enzyme linking glucose catabolism to lipogenesis by providing acetyl-CoA from mitochondrial citrate for fatty acid and cholesterol biosynthesis. Human genetic variants have been associated with enhanced growth and survival of several cancers, and with attenuated plasma triglyceride responses to dietary fish oil. In mice, liver-specific Acly deficiency protects from hepatic steatosis and dyslipidemia, whereas adipose tissue-specific Acly deletion has no phenotype, supporting therapeutic inhibition of ACLY. A lipid-regulating compound, bempedoic acid, was discovered to potently inhibit ACLY, and in animal models, it prevents dyslipidemia and attenuates atherosclerosis. Phase 2 clinical trials revealed that bempedoic acid effectively lowers LDL-C as monotherapy, combined with ezetimibe, added to statin therapy and in statin-intolerant hypercholesterolemic patients.
  
  
  CONCLUSIONS
  The efficacy of bempedoic acid as an LDL-C-lowering agent has validated ACLY inhibition as a therapeutic strategy. Positive results of phase 3 patient studies, together with long-term cardiovascular disease outcome trials, are required to establish ACLY as a major new target in cardiovascular medicine.
authors.affiliation: aDepartment of Biochemistry bDepartment of Medicine cRobarts Research Institute, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Burke
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D003998:Dicarboxylic Acids / Q000378:metabolism; D050171:Dyslipidemias / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*
chemical_list: D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D005227:Fatty Acids; C581236:8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; D001275:ATP Citrate (pro-S)-Lyase