Boston University School of Medicine, Boston, MA 02118, USA.
J Lipid Res. 2011 Sep;52(9):1693-701. doi: 10.1194/jlr.M014647. Epub 2011 Jul 8.
Recent studies have established SIRT1 as an important regulator of lipid metabolism, although the mechanism of its action at the molecular level has not been revealed. Here, we show that knockdown of SIRT1 with the help of small hairpin RNA decreases basal and isoproterenol-stimulated lipolysis in cultured adipocytes. This effect is attributed, at least in part, to the suppression of the rate-limiting lipolytic enzyme, adipose triglyceride lipase (ATGL), at the level of transcription. Mechanistically, SIRT1 controls acetylation status and functional activity of FoxO1 that directly binds to the ATGL promoter and regulates ATGL gene transcription. We have also found that depletion of SIRT1 decreases AMP-dependent protein kinase (AMPK) activity in adipocytes. To determine the input of AMPK in regulation of lipolysis, we have established a stable adipose cell line that expresses a dominant-negative α1 catalytic subunit of AMPK under the control of the inducible TET-OFF lentiviral expression vector. Reduction of AMPK activity does not have a significant effect on the rates of lipolysis in this cell model. We conclude, therefore, that SIRT1 controls ATGL transcription primarily by deacetylating FoxO1.
最近的研究已经确定 SIRT1 是脂质代谢的一个重要调节因子，尽管其在分子水平上的作用机制尚未揭示。在这里，我们表明，利用短发夹 RNA 敲低 SIRT1 会降低培养的脂肪细胞中基础状态和异丙肾上腺素刺激的脂肪分解。这种作用至少部分归因于限速脂肪酶脂肪甘油三酯脂肪酶 (ATGL) 的转录水平抑制。从机制上讲，SIRT1 控制 FoxO1 的乙酰化状态和功能活性，FoxO1 直接结合到 ATGL 启动子并调节 ATGL 基因转录。我们还发现，SIRT1 的耗竭会降低脂肪细胞中 AMP 依赖的蛋白激酶 (AMPK) 的活性。为了确定 AMPK 在脂肪分解调节中的输入，我们建立了一个稳定的脂肪细胞系，该细胞系在可诱导的 TET-OFF 慢病毒表达载体的控制下表达 AMPK 的显性失活 α1 催化亚基。在这个细胞模型中，降低 AMPK 活性对脂肪分解率没有显著影响。因此，我们得出结论，SIRT1 主要通过去乙酰化 FoxO1 来控制 ATGL 转录。
