title: Adenosine triphosphate citrate lyase: Emerging target in the treatment of dyslipidemia.
abstract: Despite major advances in pharmacologic therapy over the last few decades, dyslipidemia remains a prevalent, insufficiently recognized, and undercontrolled risk factor for cardiovascular disease. Statins are the mainstay of hypercholesterolemia treatment, but because of adherence and tolerability issues that limit dose titration, there is a need for additional therapies with good efficacy and better tolerability. Adenosine triphosphate (ATP) citrate lyase, a cytoplasmic enzyme responsible for the generation of acetyl coenzyme A for the de novo synthesis of fatty acids and cholesterol, is a very interesting molecular target for the reduction of plasma lipids. Furthermore, ATP citrate lyase inhibition may be accompanied by activation of 5'-adenosine monophosphate-activated protein kinase, a key signaling molecule that acts a central hub in cellular metabolic regulation. ETC-1002 is a small molecule inhibitor of ATP citrate lyase that also activates 5'-adenosine monophosphate-activated protein kinase, effectively reducing low-density lipoprotein cholesterol and inducing some other positive metabolic changes. Recent evidence from phase I and II clinical trials in humans has shown a positive efficacy and safety profile of ETC-1002, with low-density lipoprotein cholesterol reductions similar to those attainable by usual doses of many statins and with no major apparent side effects. These results potentially introduce a new family of medications that may expand our therapeutic arsenal against hypercholesterolemia.
authors.affiliation: Universidad de los Andes Medical School, Bogotá, Colombia.
authors.forename: Hernán N
authors.initials: HN
authors.lastname: Lemus
authors.affiliation: Universidad de los Andes Medical School, Bogotá, Colombia; Section of Endocrinology, Department of Internal Medicine, Fundación Santa Fe de Bogotá, Bogotá, Colombia. Electronic address: carlosolimpo@gmail.com.
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Mendivil
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003065:Coenzyme A / Q000096:biosynthesis; D003998:Dicarboxylic Acids / Q000627:therapeutic use*; D050171:Dyslipidemias / Q000188:drug therapy / Q000201:enzymology; D005227:Fatty Acids / Q000096:biosynthesis / Q000627:therapeutic use*; D006801:Humans
chemical_list: D003998:Dicarboxylic Acids; D005227:Fatty Acids; C581236:8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; D002784:Cholesterol; D001275:ATP Citrate (pro-S)-Lyase; D003065:Coenzyme A
keywords: AMPK; ATP citrate lyase; Cholesterol; Dyslipidemia; ETC-1002; Hypercholesterolemia; LDL; Lipid metabolism; Statin intolerance