MicroRNA 132 Regulates Nutritional Stress-Induced Chemokine Production through Repression of SirT1
MicroRNA 132 Regulates Nutritional Stress-Induced Chemokine Production through Repression of SirT1
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DOI：
10.1210/me.2009-0117
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发表时间：
2009-11-01
影响因子：
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通讯作者：
Waters, K. Michelle
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文献类型：
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作者：
Strum, Jay C.;Johnson, Jennifer H.;Waters, K. Michelle
人体脂肪组织分泌的促炎介质，可能有助于肥胖相关疾病的病理生理。了解控制其产生的调控途径对于开发治疗这些疾病的有效疗法至关重要。使用原代人脂肪源性干细胞作为前脂肪细胞和体外分化的脂肪细胞的来源，我们发现IL-8和单核细胞趋化蛋白-1（MCP-1）由两种细胞类型组成性分泌，并在血清剥夺反应中诱导。microRNA分析显示，当转换到无血清培养基时，这些细胞中microRNA 132（miR-132）的快速诱导。此外，miR-132过表达足以诱导核因子-κ B易位、p65乙酰化以及IL-8和MCP-1的产生。miR-132抑制剂降低乙酰化p65，并部分抑制血清剥夺诱导的IL-8和MCP-1的产生。miR-132显示通过SirT 1的3 '-非翻译区中的miR-132结合位点抑制沉默信息调节因子1（SirT 1）表达。因此，作为对营养可用性的响应，miR-132的诱导降低了SirT 1介导的p65的脱乙酰化，导致核因子-κ B的活化以及原代人前脂肪细胞和体外分化的脂肪细胞中IL-8和MCP-1的转录。（分子内分泌学23：1876-1884，2009）
Human adipose tissue secretes a number of proinflammatory mediators that may contribute to the pathophysiology of obesity-related disorders. Understanding the regulatory pathways that control their production is paramount to developing effective therapeutics to treat these diseases. Using primary human adipose-derived stem cells as a source of preadipocytes and in vitro differentiated adipocytes, we found IL-8 and monocyte chemoattractant protein-1 (MCP-1) are constitutively secreted by both cell types and induced in response to serum deprivation. MicroRNA profiling revealed the rapid induction of microRNA 132 (miR-132) in these cells when switched to serum-free medium. Furthermore, miR-132 overexpression was sufficient to induce nuclear factor-kappa B translocation, acetylation of p65, and production of IL-8 and MCP-1. Inhibitors of miR-132 decreased acetylated p65 and partially inhibited the production of IL-8 and MCP-1 induced by serum deprivation. MiR-132 was shown to inhibit silent information regulator 1 (SirT1) expression through a miR-132 binding site in the 3'-untranslated region of SirT1. Thus, in response to nutritional availability, induction of miR-132 decreases SirT1-mediated deacetylation of p65 leading to activation of nuclear factor-kappa B and transcription of IL-8 and MCP-1 in primary human preadipocytes and in vitro differentiated adipocytes. (Molecular Endocrinology 23: 1876-1884, 2009)