SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation
SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation
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DOI：
10.1016/j.cmet.2007.07.003
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发表时间：
2007-08-01
期刊：
影响因子：
29
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
--
作者：
Jing, Enxuan;Gesta, Stephane;Kahn, C. Ronald
哺乳动物Sirtuin蛋白家族由七个与酵母Sir2同源的成员组成。我们发现SIRT2是一种胞质sirtuin，是脂肪细胞中含量最丰富的sirtuin。在3T3-L1细胞中，前脂肪细胞分化过程中SIRT2的表达下调。过表达SIRT2抑制分化，而降低SIRT2表达促进脂肪形成。这两种作用都伴随着PPARγ、C/EBPα和标志脂肪细胞终末分化的基因表达的相应变化，包括GLUT4、aP2和脂肪酸合成酶。SIRT2降低对3T3-L1脂肪细胞的作用机制包括增加FOXO1的乙酰化，SIRT2和FOXO1之间有直接的相互作用。这种相互作用增强了胰岛素刺激的FOXO1的磷酸化，进而调节FOXO1的核和胞质定位。因此，SIRT2通过调节FOXO1的乙酰化/磷酸化和活性来调节脂肪细胞的分化，并可能在控制脂肪组织的质量和功能中发挥作用。
The family of mammalian Sirtuin proteins comprises seven members homologous to yeast Sir2. Here we show that SIRT2, a cytoplasmic sirtuin, is the most abundant sirtuin in adipocytes. Sirt2 expression is downregulated during preadipocyte differentiation in 3T3-L1 cells. Overexpression of SIRT2 inhibits differentiation, whereas reducing SIRT2 expression promotes adipogenesis. Both effects are accompanied by corresponding changes in the expression of PPAR gamma, C/EBP alpha, and genes marking terminal adipocyte differentiation, including Glut4, aP2, and fatty acid synthase. The mechanism underlying the effects of reduced SIRT2 in 3T3-L1 adipocytes includes increased acetylation of FOXO1, with direct interaction between SIRT2 and FOXO1. This interaction enhances insulin-stimulated phosphorylation of FOXO1, which in turn regulates FOXO1 nuclear and cytosolic localization. Thus, Sirt2 acts as an important regulator of adipocyte differentiation through modulation of FOXO1 acetylation/phosphorylation and activity and may play a role in controlling adipose tissue mass and function.