Hepatic de novo lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive ¹³C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.

中文翻译：

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利用丙酮酸、乙酸盐和酮体的分层肝脏从头脂肪生成底物供应网络


肝脏新发脂肪生成 （DNL） 是一个基本的生理过程，在代谢性疾病中通常呈致病性升高。由于对提供胞质乙酰辅酶 A（DNL 的专性前体）的代谢途径不完全了解，包括它们的相互作用和比例贡献，治疗受到限制。在这里，我们将广泛的 ¹³C 示踪与介导胞质乙酰辅酶 A 产生的关键线粒体和胞质蛋白的肝脏特异性敲除相结合。我们表明，线粒体丙酮酸载体 （MPC） 和 ATP-柠檬酸裂解酶 （ACLY） 是肝脏脂肪生成乙酰辅酶 A 产生的主要途径，与乙酰辅酶 A 合成酶 2 （ACSS2） 平行运作。鉴于线粒体柠檬酸盐载体 （CiC） 和 ACSS2 双敲除后的持续 DNL，我们测试了外源性和亮氨酸衍生的乙酰乙酸酯对乙酰乙酰辅酶 A 合成酶 （AACS） 依赖性 DNL 的贡献。CiC 敲除增加了乙酰乙酸提供的肝脏乙酰辅酶 A 产生和 DNL，表明酮体作为线粒体-柠檬酸盐互惠 DNL 前体发挥作用。通过描绘线粒体-胞质溶质 DNL 底物供应网络，这些发现可能为治疗调节 DNL 的策略提供信息。