Liu Joyce Y, Kuna Ramya S, Pinheiro Laura V, Nguyen Phuong T T, Welles Jaclyn E, Drummond Jack M, Murali Nivitha, Sharma Prateek V, Supplee Julianna G, Shiue Mia, Zhao Steven, Farria Aimee T, Kumar Avi, Ruchhoeft Mauren L, Demetriadou Christina, Kantner Daniel S, Chatoff Adam, Megill Emily, Titchenell Paul M, Snyder Nathaniel W, Metallo Christian M, Wellen Kathryn E
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Molecular and Cell Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Metab. 2025 Jan 7;37(1):239-254.e7. doi: 10.1016/j.cmet.2024.10.014. Epub 2024 Oct 28.
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.
ATP柠檬酸裂解酶（ACLY）为从头脂肪生成（DNL）合成乙酰辅酶A，在代谢功能障碍相关脂肪性肝病中该酶水平升高。肝脏ACLY受降低低密度脂蛋白胆固醇的药物贝派地酸（BPA）抑制，BPA还可改善小鼠的脂肪变性。虽然BPA能有效抑制肝脏DNL并增加脂肪分解代谢，但尚不清楚ACLY是否是其降低肝脏甘油三酯的主要分子靶点。我们发现，在西式饮食条件下，单独缺失肝脏ACLY或与乙酰辅酶A合成酶ACSS2共同缺失，意外地加剧了脂肪变性，这与过氧化物酶体增殖物激活受体α（PPARα）靶基因表达降低和脂肪酸氧化减少有关。重要的是，BPA处理改善了西式饮食介导的野生型和肝脏ACLY基因敲除小鼠的甘油三酯积累，表明其对肝脏脂肪变性的主要作用不依赖于ACLY。总之，这些数据表明肝脏ACLY在抑制饮食依赖性脂质积累中发挥了意想不到的作用，并且BPA在不依赖ACLY的情况下对肝脏脂质代谢产生显著影响。
