SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism
SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism
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DOI：
10.1074/jbc.m110.122978
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发表时间：
2010-10-29
影响因子：
4.8
通讯作者：
Kemper, Jongsook Kim
中科院分区：
文献类型：
--
作者：
Ponugoti, Bhaskar;Kim, Dong-Hyun;Kemper, Jongsook Kim
SIRT1 脱乙酰酶可抑制脂肪合成并刺激脂肪氧化以响应禁食，但其潜在机制仍不清楚。在此，我们报道 SREBP-1c（一种关键的脂肪生成激活剂）是 SIRT1 的体内靶点。 SIRT1 与 SREBP-1c 的相互作用在禁食期间增加，在进食时减少，并且一致地，在小鼠肝脏中，禁食期间 SREBP-1c 乙酰化水平降低。在用胰岛素和葡萄糖模拟喂养条件处理的 HepG2 细胞中，乙酰化的 SREBP-1c 水平也有所增加，并且 siRNA 下调 p300 降低了乙酰化。腺病毒 siRNA 消耗肝脏 SIRT1 会增加 SREBP-1c 的乙酰化，从而增加脂肪生成基因的表达。串联质谱和诱变研究表明，SREBP-1c 在 Lys-289 和 Lys-309 处被 p300 乙酰化。使用乙酰化缺陷突变体进行的机制研究表明，SIRT1 通过降低 SREBP-1c 的稳定性及其在脂肪生成基因中的占据来去乙酰化并抑制 SREBP-1c 反式激活。值得注意的是，在饮食诱导的肥胖小鼠中，SREBP-1c 乙酰化水平升高，肝脏过度表达 SIRT1 或使用白藜芦醇（一种 SIRT1 激活剂）治疗，每天持续 1 周，可降低乙酰化 SREBP-1c 水平，从而产生有益的功能结果。这些结果表明，SREBP-1c 乙酰化升高与脂肪生成基因表达增加之间存在有趣的联系，表明异常升高的 SREBP-1c 乙酰化会增加肥胖小鼠的 SREBP-1c 脂肪生成活性。通过靶向 SIRT1 减少 SREBP-1c 的乙酰化可能有助于治疗代谢性疾病，包括脂肪肝、肥胖和 II 型糖尿病。
The SIRT1 deacetylase inhibits fat synthesis and stimulates fat oxidation in response to fasting, but the underlying mechanisms remain unclear. Here we report that SREBP-1c, a key lipogenic activator, is an in vivo target of SIRT1. SIRT1 interaction with SREBP-1c was increased during fasting and decreased upon feeding, and consistently, SREBP-1c acetylation levels were decreased during fasting in mouse liver. Acetylated SREBP-1c levels were also increased in HepG2 cells treated with insulin and glucose to mimic feeding conditions, and down-regulation of p300 by siRNA decreased the acetylation. Depletion of hepatic SIRT1 by adenoviral siRNA increased acetylation of SREBP-1c with increased lipogenic gene expression. Tandem mass spectrometry and mutagenesis studies revealed that SREBP-1c is acetylated by p300 at Lys-289 and Lys-309. Mechanistic studies using acetylation-defective mutants showed that SIRT1 deacetylates and inhibits SREBP-1c transactivation by decreasing its stability and its occupancy at the lipogenic genes. Remarkably, SREBP-1c acetylation levels were elevated in diet-induced obese mice, and hepatic overexpression of SIRT1 or treatment with resveratrol, a SIRT1 activator, daily for 1 week decreased acetylated SREBP-1c levels with beneficial functional outcomes. These results demonstrate an intriguing connection between elevated SREBP-1c acetylation and increased lipogenic gene expression, suggesting that abnormally elevated SREBP-1c acetylation increases SREBP-1c lipogenic activity in obese mice. Reducing acetylation of SREBP-1c by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes.