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.

乙酰辅酶 A 羧化酶 (ACC) 通过产生丙二酰辅酶 A 促进膳食肝脏代谢，丙二酰辅酶 A 是从头脂肪生成的底物，也是 CPT-1 介导的脂肪氧化的抑制剂。我们报告说，抑制 ACC 还会对代谢产生意想不到的次级影响。肝脏特异性双 ACC1/2 敲除 (LDKO) 或 ACC 的药物抑制通过激活进食状态下的肝脏 CPT-1 和丙酮酸羧化酶通量来增加回补、三羧酸 (TCA) 循环中间体和糖异生。禁食本应使 ACC 的作用边缘化，但 LDKO 小鼠在禁食期间保持 TCA 循环中间体升高并维持血糖水平。这些效应伴随着补偿性诱导蛋白水解和增加糖异生的氨基酸供应，而这被摄食期间蛋白质合成的增加所抵消。这种适应可能与 Nrf2 活性有关，Nrf2 活性是由 ACC 抑制诱导的，并与空腹氨基酸相关。这些发现揭示了肝脏中丙二酰辅酶A合成的意想不到的作用，并提供了对药理学ACC抑制的更广泛影响的深入了解。