Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia.

肝脏从头升高脂肪生成有助于非酒精性脂肪性肝炎 (NASH)，并且可以通过靶向乙酰辅酶 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，但抑制是否对治疗 NASH 有效尚不清楚。在这里，我们描述了一种新的小鼠模型，该模型复制了 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、脂肪变性和气球样变以及血糖、甘油三酯和胆固醇。ACLY 的药理学抑制与遗传抑制相似，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 生物标志物有关。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。