SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity
SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity
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DOI：
10.1152/ajpendo.00417.2009
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发表时间：
2010-03-01
影响因子：
5.1
通讯作者：
Olefsky, Jerrold M.
中科院分区：
文献类型：
--
作者：
Yoshizaki, Takeshi;Schenk, Simon;Olefsky, Jerrold M.
Yoshizaki T, Schenk S, Imamura T, Babendure JL, Sonoda N, Bae EJ, Oh DY, Lu M, Milne JC, Westphal C, Bandyopadhyay G, Olefsky JM。SIRT1抑制巨噬细胞炎症通路并调节胰岛素敏感性。[J] .中国生物医学工程学报，2016,31(2):559 - 564。首次发表于2009年12月8日；doi: 10.1152 / ajpendo.00417.2009。慢性炎症是胰岛素抵抗和2型糖尿病等肥胖相关疾病的重要病因，最近的研究表明，巨噬细胞可能是导致这种慢性炎症状态的起始细胞类型。哺乳动物沉默信息调节因子2的同源物SIRT1调节了几个对寿命重要的生理过程，并且SIRT1在调节胰岛素敏感性方面的潜在作用已被证明。然而，在炎症方面，SIRT1在巨噬细胞内调节促炎通路中的作用尚不清楚。本研究表明，小鼠巨噬细胞RAW264.7细胞系和腹腔巨噬细胞中SIRT1的下调广泛激活JNK和IKK炎症通路，并增加lps刺激的TNF α分泌。此外，基因表达谱显示SIRT1敲低导致炎症基因表达增加。我们还证明SIRT1激活剂在RAW264.7细胞和原代腹腔巨噬细胞中以SIRT1依赖的方式抑制lps刺激的炎症途径以及TNF α的分泌。在葡萄糖钳夹研究中，用SIRT1激活剂治疗Zucker脂肪大鼠可显著改善葡萄糖耐量，降低高胰岛素血症，并增强全身胰岛素敏感性。这些体内胰岛素增敏作用伴随着组织炎症标志物的减少和脂肪组织巨噬细胞促炎状态的减少，与SIRT1在巨噬细胞中的体外作用完全一致。总之，这些结果确定了SIRT1作为胰岛素抵抗背景下巨噬细胞炎症反应的重要调节因子的新作用，并提出了靶向SIRT1可能是治疗代谢性疾病炎症成分的有用策略的可能性。
Yoshizaki T, Schenk S, Imamura T, Babendure JL, Sonoda N, Bae EJ, Oh DY, Lu M, Milne JC, Westphal C, Bandyopadhyay G, Olefsky JM. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab 298: E419-E428, 2010. First published December 8, 2009; doi:10.1152/ajpendo.00417.2009.-Chronic inflammation is an important etiology underlying obesity-related disorders such as insulin resistance and type 2 diabetes, and recent findings indicate that the macrophage can be the initiating cell type responsible for this chronic inflammatory state. The mammalian silent information regulator 2 homolog SIRT1 modulates several physiological processes important for life span, and a potential role of SIRT1 in the regulation of insulin sensitivity has been shown. However, with respect to inflammation, the role of SIRT1 in regulating the proinflammatory pathway within macrophages is poorly understood. Here, we show that knockdown of SIRT1 in the mouse macrophage RAW264.7 cell line and in intraperitoneal macrophages broadly activates the JNK and IKK inflammatory pathways and increases LPS-stimulated TNF alpha secretion. Moreover, gene expression profiles reveal that SIRT1 knockdown leads to an increase in inflammatory gene expression. We also demonstrate that SIRT1 activators inhibit LPS-stimulated inflammatory pathways, as well as secretion of TNF alpha, in a SIRT1-dependent manner in RAW264.7 cells and in primary intraperitoneal macrophages. Treatment of Zucker fatty rats with a SIRT1 activator leads to greatly improved glucose tolerance, reduced hyperinsulinemia, and enhanced systemic insulin sensitivity during glucose clamp studies. These in vivo insulin-sensitizing effects were accompanied by a reduction in tissue inflammation markers and a decrease in the adipose tissue macrophage proinflammatory state, fully consistent with the in vitro effects of SIRT1 in macrophages. In conclusion, these results define a novel role for SIRT1 as an important regulator of macrophage inflammatory responses in the context of insulin resistance and raise the possibility that targeting of SIRT1 might be a useful strategy for treating the inflammatory component of metabolic diseases.