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JBC:研究发现阻断蛋白SirT1与谷胱甘肽反应可规避代谢性疾病

来源:生物谷 2014-01-28 20:56

2014年1月28日讯 /生物谷BIOON/--近日,研究人员发现改变蛋白SirT1可以防止过量代谢应激相关的肥胖,糖尿病和衰老。

研究表明,蛋白SirT1可能在代谢性疾病中起到保护性作用,并对老化有影响,SirT1活动的减少已在各种疾病模型,包括糖尿病和代谢综合征中得到证实。保持该蛋白的正常水平,可有效预防肥胖和年龄相关疾病。

肥胖症,糖尿病和老化引起的代谢性应激会增加一个小分子,谷胱甘肽,用SirT1处理,能抑制谷胱甘肽活性。在Journal of Biological Chemistry杂志在公布的这项研究结果中,研究人员已经证明,通过改变SirT1的三个氨基酸,他们可能会产生一个“超级SirT1”,其在代谢应激情况下仍能正常运作。

此研究确立了过量代谢有关的应激可通过改变蛋白质SirT1,或通过防止蛋白质SirT1与谷胱甘肽反应被规避。(生物谷Bioon.com)

 

A redox-resistant sirtuin-1 mutant protects against hepatic metabolic and oxidant stress.

D. Shao, J. L. Fry, J. Han, X. Hou, D. R. Pimentel, R. Matsui, R. A. Cohen, M. M. Bachschmid.

Sirtuin-1 (SirT1), a member of the NAD+-dependent class III histone deacetylase family, is inactivated in vitro by oxidation of critical cysteine thiols. In a model of metabolic disease, SirT1 activation attenuated apoptosis of hepatocytes and improved liver function including insulin and lipid metabolism. We show in SirT1 overexpressing HepG2 cells that oxidants (nitrosocysteine or hydrogen peroxide) or metabolic stress (high palmitate and high glucose) inactivate SirT1 by reversible oxidative post-translational modifications (OPTM) on cysteines. Mutating these oxidation-sensitive cysteines to serine preserves SirT1 activity and abolishes reversible OPTMs. Overexpressed mutant SirT1 maintains deacetylase activity and attenuates proapoptotic signaling, while overexpressed wild type SirT1 is less protective in metabolically or oxidant stressed cells. To prove that OPTMs of SirT1 are glutathione (GSH) adducts, glutaredoxin-1 (Glrx) was overexpressed to remove this modification. Glrx overexpression maintains endogenous SirT1 activity and prevents proapoptotic signaling in metabolically stressed HepG2 cells. The in vivo significance of oxidative inactivation of SirT1 was investigated in livers of high fat diet-fed C57/B6J mice. SirT1 deacetylase activity was decreased in the absence of changes in SirT1 expression and associated with a marked increase in OPTMs. These results indicate that glutathione adducts on specific SirT1 thiols may be responsible for dysfunctional SirT1 associated with liver disease in metabolic syndrome.

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