乙酰辅酶 A 羧化酶 1 是脂肪细胞产热程序的抑制剂。

Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.

机构信息

Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.

出版信息

Cell Rep. 2023 May 30;42(5):112488. doi: 10.1016/j.celrep.2023.112488. Epub 2023 May 8.

Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in addition to depletion of palmitate. We explore which of these metabolite changes triggers adipose browning by generating eight adipose-selective KO mouse models with loss of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), ACC2, malonyl-CoA decarboxylase (MCD) or FASN, or dual KOs ACLY/FASN, ACC1/FASN, and ACC2/FASN. Preventing elevation of acetyl-CoA and malonyl-CoA by depletion of adipocyte ACLY or ACC1 in combination with FASN KO does not block the browning of iWAT. Conversely, elevating malonyl-CoA levels in MCD KO mice does not induce browning. Strikingly, adipose ACC1 KO induces a strong iWAT thermogenic response similar to FASN KO while also blocking malonyl-CoA and palmitate synthesis. Thus, ACC1 and FASN are strong suppressors of adipocyte thermogenesis through promoting lipid synthesis rather than modulating the DNL intermediates acetyl-CoA or malonyl-CoA.

脂肪酸合酶（FASN）在脂肪细胞中的缺失会破坏从头合成脂肪酸（DNL），从而诱导腹股沟白色脂肪组织（iWAT）的棕色化。然而，脂肪细胞 FASN 敲除（KO）除了耗尽棕榈酸外，还会增加乙酰辅酶 A（CoA）和丙二酰 CoA。我们通过生成 8 种脂肪组织选择性 KO 小鼠模型来探索这些代谢物变化中的哪一种触发了脂肪棕色化，这些模型分别缺失了 ATP-柠檬酸裂解酶（ACLY）、乙酰辅酶 A 羧化酶 1（ACC1）、ACC2、丙二酰 CoA 脱羧酶（MCD）或 FASN，或同时缺失 ACLY 和 FASN、ACC1 和 FASN、以及 ACC2 和 FASN。通过脂肪细胞 ACLY 或 ACC1 的缺失与 FASN KO 联合来防止乙酰 CoA 和丙二酰 CoA 的升高，并不能阻止 iWAT 的棕色化。相反，在 MCD KO 小鼠中升高丙二酰 CoA 水平并不会诱导棕色化。引人注目的是，脂肪细胞 ACC1 KO 诱导了与 FASN KO 相似的强烈 iWAT 产热反应，同时也阻止了丙二酰 CoA 和棕榈酸的合成。因此，ACC1 和 FASN 通过促进脂质合成而不是调节 DNL 中间产物乙酰 CoA 或丙二酰 CoA，是脂肪细胞产热的强有力抑制剂。