Inhibition of acetyl-CoA carboxylases by soraphen A prevents lipid accumulation and adipocyte differentiation in 3T3-L1 cells
Inhibition of acetyl-CoA carboxylases by soraphen A prevents lipid accumulation and adipocyte differentiation in 3T3-L1 cells
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DOI：
10.1016/j.ejphar.2016.03.052
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发表时间：
2016-06-05
影响因子：
5
通讯作者：
Zempleni, Janos
中科院分区：
文献类型：
--
作者：
Cordonier, Elizabeth L.;Jarecke, Sarah K.;Zempleni, Janos
乙酰辅酶a羧化酶（ACC） 1和2催化乙酰辅酶a羧化为丙二酰辅酶a，并依赖于生物素作为辅酶。ACC1定位于细胞质并产生丙二酰辅酶a用于脂肪酸（FA）的合成。ACC2定位于线粒体外膜，产生丙二酰辅酶a，抑制FA进入线粒体进行随后的氧化。我们假设ACCs是脂肪细胞分化的检查点，并在小鼠3T3-L1前脂肪细胞中使用ACC1和ACC2抑制剂soraphen A （SA）来验证这一假设。3T3-L1细胞诱导分化后用100 nM SA处理8 d，与溶剂对照相比，PPARy mRNA和FABP4 mRNA的表达分别下降40%和50%；基因表达的减少伴随着FABP4蛋白表达的减少，并与脂滴积累的减少有关。与对照相比，sa处理的细胞FA氧化率提高了300%。外源棕榈酸处理恢复了SA处理细胞中PPARy和FABP4 mRNA的表达以及FABP4蛋白的表达。相反，如果在诱导分化后第8天开始治疗，SA不会改变脂质积累。我们得出结论，失去acc1依赖性FA合成和失去acc2依赖性FA氧化抑制可阻止脂肪细胞中的脂质积累并抑制脂肪细胞分化的早期阶段。(C) 2016 Elsevier B.V.版权所有
Acetyl-CoA carboxylases (ACC) 1 and 2 catalyze the carboxylation of acetyl-CoA to malonyl-CoA and depend on biotin as a coenzyme. ACC1 localizes in the cytoplasm and produces malonyl-CoA for fatty acid (FA) synthesis. ACC2 localizes in the outer mitochondrial membrane and produces malonyl-CoA that inhibits FA import into mitochondria for subsequent oxidation. We hypothesized that ACCs are checkpoints in adipocyte differentiation and tested this hypothesis using the ACC1 and ACC2 inhibitor soraphen A (SA) in murine 3T3-L1 preadipocytes. When 3T3-L1 cells were treated with 100 nM SA for 8 days after induction of differentiation, the expression of PPARy mRNA and FABP4 mRNA decreased by 40% and 50%, respectively, compared with solvent controls; the decrease in gene expression was accompanied by a decrease in FABP4 protein expression and associated with a decrease in lipid droplet accumulation. The rate of FA oxidation was 300% greater in SA-treated cells compared with vehicle controls. Treatment with exogenous palmitate restored PPARy and FABP4 mRNA expression and FABP4 protein expression in SA treated cells. In contrast, SA did not alter lipid accumulation if treatment was initiated on day eight after induction of differentiation. We conclude that loss of ACC1-dependent FA synthesis and loss of ACC2dependent inhibition of FA oxidation prevent lipid accumulation in adipocytes and inhibit early stages of adipocyte differentiation. (C) 2016 Elsevier B.V. All rights reserved.