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.

中文翻译：

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Bempedoic acid 抑制饮食诱导的肝脂肪变性，独立于 ATP-柠檬酸盐裂解酶


ATP 柠檬酸裂解酶 （ACLY） 合成乙酰辅酶 A 用于从头脂肪生成 （DNL），在代谢功能障碍相关的脂肪性肝病中，DNL 升高。肝脏 ACLY 被降低 LDL 胆固醇的药物 bempedoic acid （BPA） 抑制，该药物还可以改善小鼠的脂肪变性。虽然 BPA 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标。我们表明，在西方饮食中，肝脏 ACLY 单独丢失或与乙酰辅酶 A 合成酶 ACSS2 一起丢失会意外加剧脂肪变性，这与 PPARα 靶基因表达和脂肪酸氧化降低有关。重要的是，BPA 治疗改善了 WT 和肝脏 ACLY 敲除小鼠中西方饮食介导的三酰甘油酯积累，表明其对肝脂肪变性的主要影响是 ACLY 独立的。总之，这些数据表明，肝脏 ACLY 在抑制饮食依赖性脂质积累方面发挥着意想不到的作用，并且 BPA 对肝脏脂质代谢产生重大影响，独立于 ACLY。