新靶点三磷酸腺苷柠檬酸裂解酶(ACLY)抑制剂用于降血脂的研究进展

Research progress on ATP citrate lyase(ACLY)inhibitors for decreasing blood lipids

心血管疾病是全世界发病和死亡的主要疾病之一。尽管药物治疗在过去几十年中取得了重大进展,但心血管疾病的预防与治疗还存在很多不足之处,其中血脂异常仍然是心血管疾病的一个普遍危险特征,它还没有得到足够的认识和控制。越来越多的证据显示,心血管疾病的发生发展与许多其他独立的危险因素,如偏高的低密度脂蛋白水平、偏低的高密度脂蛋白水平以及高甘油三酯水平有关。血脂异常患者的多项临床试验表明,积极降低低密度脂蛋白胆固醇(LDL-C)可以显著减少心血管疾病事件。三磷酸腺苷柠檬酸裂解酶(ACLY)是一种胞质同源四聚体酶,在三磷酸腺苷(ATP)的作用下,ACLY可以催化柠檬酸和辅酶A转化为乙酰辅酶A和草酰乙酸酯。由于ACLY是产生胞浆乙酰辅酶A的主要酶,而胞浆乙酰辅酶A是胆固醇和脂肪酸从头合成所需的前体,因此抑制ACLY有可能达到减少乙酰辅酶A的生成从而降低胆固醇以及甘油三酯水平的目的。目前ACLY可作为降低血脂的一个分子靶标,人们对ACLY抑制剂的研究也越来越多。本文简单介绍了ACLY的结构、作用机制以及与脂质代谢之间的关系,并对目前的一些ACLY抑制剂进行了综述。

Cardiovascular disease is a principal cause of morbidity and death in the world.Although drug therapy has made great progress in the past few decades,there are still many deficiencies in the prevention and treatment of cardiovascular disease.Dyslipidemia is still a common risk feature and is not sufficiently controlled.A growing body of evidence suggests that the occurrence and development of cardiovascular disease is associated with many associated risk factors,such as higher low-density lipoprotein levels,lower high-density lipoprotein levels and high triglyceride levels.A number of clinical trials in patients with dyslipidemia have shown that actively decreasing low density lipoprotein cholesterol can significantly decrease cardiovascular events.ATP citrate lyase(ACLY)is a cytoplasmic homo-tetrameric enzyme.In the presence of adenosine triphosphate(ATP),ACLY catalyzes the conversion of citric acid and coenzyme A to acetyl-CoA and oxalyl acetate.ACLY is the main enzyme for the production of cytoplasmic acetyl-CoA,and cytoplasmic acetyl-CoA is the precursor required for de novo synthesis of cholesterol and fatty acids.Therefore,it is possible to reduce the production of acetyl-CoA and reduce the levels of cholesterol and triglycerides by inhibiting ACLY.ACLY can be used as a molecular target for reducing blood lipids,and there are an increasing number of studies on ACLY inhibitors.In this paper,the structure and mechanism of ACLY and its relationship with lipid metabolism are briefly introduced,and we review some current ACLY inhibitors.