美国宾夕法尼亚大学Kathryn E. Wellen等研究人员合作发现，贝派地酸不依赖于ATP-柠檬酸裂解酶抑制饮食诱导的肝脏脂肪变性。相关论文于2024年10月28日在线发表在《细胞—代谢》杂志上。

研究人员表示，ATP柠檬酸裂解酶（ACLY）合成乙酰辅酶A，用于新生脂肪生成（DNL），其在与代谢功能障碍相关的脂肪肝疾病中升高。

肝脏ACLY受到降LDL胆固醇药物贝派地酸（BPA）的抑制，后者在小鼠中也改善了脂肪肝。

尽管BPA有效抑制肝脏DNL并增加脂肪分解，但尚不清楚ACLY是否是其减少肝脏甘油三酯的主要分子靶点。

研究人员表明，在西方饮食下，单独缺失肝脏ACLY或与乙酰辅酶A合成酶ACSS2一起缺失意外地加重了脂肪肝，这与PPARα靶基因表达减少和脂肪酸氧化有关。

重要的是，BPA处理改善了西方饮食引起的三酰甘油积累，无论是在野生型小鼠还是肝脏ACLY基因敲除小鼠中，表明其对肝脏脂肪肝的主要影响与ACLY无关。

综合这些数据表明，肝脏ACLY在抑制饮食依赖的脂质积累方面发挥了意外的作用，而BPA则对肝脏脂质代谢产生了显著影响，且不依赖于ACLY。

附：英文原文

Title: Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase

Author: Joyce Y. Liu, Ramya S. Kuna, Laura V. Pinheiro, Phuong T.T. Nguyen, Jaclyn E. Welles, Jack M. Drummond, Nivitha Murali, Prateek Sharma, Julianna G. Supplee, Mia Shiue, Steven Zhao, Aimee T. Farria, Avi Kumar, Mauren L. Ruchhoeft, Christina Demetriadou, Daniel S. Kantner, Adam Chatoff, Emily Megill, Paul M. Titchenell, Nathaniel W. Snyder, Christian M. Metallo, Kathryn E. Wellen

Issue&Volume: 2024-10-28

Abstract: ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.

DOI: 10.1016/j.cmet.2024.10.014

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00410-8