Burke Amy C, Huff Murray W
aDepartment of Biochemistry bDepartment of Medicine cRobarts Research Institute, The University of Western Ontario, London, Ontario, Canada.
Curr Opin Lipidol. 2017 Apr;28(2):193-200. doi: 10.1097/MOL.0000000000000390.
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.
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.
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.
ATP柠檬酸裂解酶（ACLY）已再度成为降低低密度脂蛋白胆固醇（LDL-C）的药物靶点。我们综述了将ACLY作为一种治疗策略的相关内容，包括其遗传学、分子和细胞生物学以及对它的抑制作用。
ACLY是一种关键酶，通过从线粒体柠檬酸提供乙酰辅酶A用于脂肪酸和胆固醇生物合成，将葡萄糖分解代谢与脂肪生成联系起来。人类遗传变异与多种癌症的生长和存活增强以及血浆甘油三酯对膳食鱼油的反应减弱有关。在小鼠中，肝脏特异性Acly缺陷可预防肝脂肪变性和血脂异常，而脂肪组织特异性Acly缺失则无表型，这支持了对ACLY的治疗性抑制。发现一种脂质调节化合物苯培多酸可有效抑制ACLY，在动物模型中，它可预防血脂异常并减轻动脉粥样硬化。2期临床试验表明，苯培多酸作为单一疗法、与依折麦布联合使用、添加到他汀类药物治疗中以及在不耐受他汀类药物的高胆固醇血症患者中，均可有效降低LDL-C。
苯培多酸作为降低LDL-C药物的疗效已证实抑制ACLY是一种治疗策略。需要3期患者研究的阳性结果以及长期心血管疾病结局试验，才能将ACLY确立为心血管医学中的一个主要新靶点。
