小柯机器人

美国德克萨斯大学西南医学中心Shawn C. Burgess和Jay D. Horton研究组发现，肝脏产生的丙二酰-CoA通过抑制脂肪氧化、丙酮酸羧化和氨基酸可及性来抑制糖异生。相关论文于2024年3月5日发表在《细胞-代谢》杂志上。

研究人员发现抑制乙酰-CoA羧化酶（ACC）还会对新陈代谢产生意外的副作用。肝脏特异性双ACC1/2基因敲除（LDKO）或药物抑制ACC可通过激活肝脏CPT-1和增加丙酮酸羧化酶，在进食状态下增加胰岛素生成、三羧酸（TCA）循环中间产物和葡萄糖生成。禁食本应使ACC的作用边缘化，但LDKO小鼠在禁食期间会产生TCA循环中间产物升高和血糖的稳定。

这些会诱导代偿性蛋白质分解和葡萄糖生成所需氨基酸供应增加，而这又被进食时蛋白质合成的增加所抵消。这种适应性可能与Nrf2活性有关，Nrf2活性由ACC抑制诱导，并与禁食氨基酸相关。这些发现揭示了丙二酰-CoA合成在肝脏中的独特的作用，并为ACC抑制剂的更广泛应用提供了见解。

据了解，ACC通过产生丙二酰-CoA（脂肪合成的底物和CPT-1介导的脂肪氧化抑制剂）来促进肝脏膳食代谢。

附：英文原文

Title: Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability

Author: Stanislaw Deja, Justin A. Fletcher, Chai-Wan Kim, Blanka Kucejova, Xiaorong Fu, Monika Mizerska, Morgan Villegas, Natalia Pudelko-Malik, Nicholas Browder, Melissa Inigo-Vollmer, Cameron J. Menezes, Prashant Mishra, Eric D. Berglund, Jeffrey D. Browning, John P. Thyfault, Jamey D. Young, Jay D. Horton, Shawn C. Burgess

Issue&Volume: 2024-03-05

Abstract: Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition of ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic inhibition of ACC increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, and gluconeogenesis by activating hepatic CPT-1 and pyruvate carboxylase flux in the fed state. Fasting should have marginalized the role of ACC, but LDKO mice maintained elevated TCA cycle intermediates and preserved glycemia during fasting. These effects were accompanied by a compensatory induction of proteolysis and increased amino acid supply for gluconeogenesis, which was offset by increased protein synthesis during feeding. Such adaptations may be related to Nrf2 activity, which was induced by ACC inhibition and correlated with fasting amino acids. The findings reveal unexpected roles for malonyl-CoA synthesis in liver and provide insight into the broader effects of pharmacologic ACC inhibition.

DOI: 10.1016/j.cmet.2024.02.004

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00050-0

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