美国爱荷华大学卡佛医学院Eric B. Taylor团队近期取得重要工作进展，他们研究提出，利用丙酮酸、乙酸和酮的分级肝脏从头脂肪生成底物供应网络。相关研究成果2024年10月28日在线发表于《细胞—代谢》杂志上。

据介绍，肝脏新生脂肪生成（DNL）是一种基本的生理过程，在代谢性疾病中通常会升高。治疗受到对供应细胞溶质乙酰辅酶A（DNL的专性前体）的代谢途径的不完全理解的限制，包括它们的相互作用和比例贡献。

研究人员将广泛的¹³C追踪与介导细胞质乙酰辅酶A产生的关键线粒体和细胞质蛋白的肝脏特异性敲除相结合。研究人员发现，线粒体丙酮酸载体（MPC）和ATP柠檬酸裂解酶（ACLY）控制着主要的肝脏脂肪生成乙酰辅酶A的产生途径，与乙酰辅酶A合成酶2（ACS2）并行运作。

在线粒体柠檬酸盐载体（CiC）和ACS2双重敲除后持续DNL的情况下，研究人员测试了外源性和亮氨酸来源的乙酰乙酸，对乙酰乙酰辅酶A合成酶（AACS）依赖性DNL的贡献。CiC基因敲除增加了乙酰乙酸供应的肝脏乙酰-CoA产量和DNL，表明酮体具有线粒体-柠檬酸互作 DNL 前体的功能。通过描绘线粒体-细胞质DNL底物供应网络，这一研究可能为治疗性调节DNL的策略提供信息。

附：英文原文

Title: A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones

Author: Adam J. Rauckhorst, Ryan D. Sheldon, Daniel J. Pape, Adnan Ahmed, Kelly C. Falls-Hubert, Ronald A. Merrill, Reid F. Brown, Kshitij Deshmukh, Thomas A. Vallim, Stanislaw Deja, Shawn C. Burgess, Eric B. Taylor

Issue&Volume: 2024-10-28

Abstract: 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.

DOI: 10.1016/j.cmet.2024.10.013

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00409-1