加拿大麦克马斯特大学Gregory R. Steinberg团队近期取得重要工作进展，他们研究发现抑制ATP-柠檬酸裂解酶可改善NASH、肝纤维化和血脂异常。该项研究成果2022年6月7日在线发表于《细胞—代谢》杂志上。

在这里，研究人员描述了一种新的小鼠模型，该模型再现了NASH的许多病理和分子驱动因素，并发现通过基因抑制肝细胞中的ACLY可降低肝脏丙二酰辅酶A、草酰乙酸、脂肪变性和肿胀以及血糖、甘油三酯和胆固醇。ACLY的药理抑制与遗传抑制类似，但对肝星状细胞、肝脏炎症和纤维化具有额外的积极作用。模拟ACLY降低的人类变异的孟德尔随机化也与较低的循环甘油三酯和NASH生物标志物相关。这些数据表明，抑制肝脏ACLY可能是治疗NASH和血脂异常的有效方法。

据介绍，肝脏从头脂肪生成升高会有助于非酒精性脂肪性肝炎(NASH)，可通过靶向乙酰辅酶A羧化酶(ACC)来抑制。然而，高甘油三酯血症限制了药理学ACC抑制剂作为单一治疗法的使用。ATP-柠檬酸裂解酶(ACLY)从柠檬酸盐中生成乙酰辅酶A和草酰乙酸，但抑制作用是否对NASH有效尚不清楚。

附：英文原文

Title: Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia

Author: Marisa R. Morrow, Battsetseg Batchuluun, Jianhan Wu, Elham Ahmadi, Julie M. Leroux, Pedrum Mohammadi-Shemirani, Eric M. Desjardins, Zhichao Wang, Evangelia E. Tsakiridis, Declan C.T. Lavoie, Amir Reihani, Brennan K. Smith, Jacek M. Kwiecien, James S.V. Lally, Tracy L. Nero, Michael W. Parker, Kjetil Ask, John W. Scott, Lei Jiang, Guillaume Paré, Stephen L. Pinkosky, Gregory R. Steinberg

Issue&Volume: 2022/06/07

Abstract: Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibitedby targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits theuse of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generatesacetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective fortreating NASH is unknown. Here, we characterize a new mouse model that replicatesmany of the pathological and molecular drivers of NASH and find that genetically inhibitingACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooningas well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibitionof ACLY mirrors genetic inhibition but has additional positive effects on hepaticstellate cells, liver inflammation, and fibrosis. Mendelian randomization of humanvariants that mimic reductions in ACLY also associate with lower circulating triglyceridesand biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effectiveapproach for treatment of NASH and dyslipidemia.

DOI: 10.1016/j.cmet.2022.05.004

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00186-3