郭非凡研究组发现丝氨酸在胰岛素敏感性调控中的作用

　　

   2014年12月12日，中国科学院上海生命科学研究院营养科学研究所郭非凡组在国际学术期刊Diabetes上发表题为Hepatic phosphoserine aminotransferase 1 (PSAT1) regulates insulin sensitivity in mice via tribbles homolog 3 (TRB) 的论文，发现了非必需氨基酸丝氨酸在胰岛素敏感性调控中的重要作用。

　　胰岛素抵抗是2型糖尿病发生的主要特征，而营养因素在胰岛素抵抗的发生中起到至关重要的作用。研究曾发现，无论在动物还是人群中，必需氨基酸尤其是支链氨基酸水平和胰岛素抵抗的发生密切相关。但是非必需氨基酸及其合成酶对胰岛素敏感性的影响却未引起人们的关注。丝氨酸作为一种非必需氨基酸，其合成途径在各种生物过程中的作用受到越来越多的重视，但是在胰岛素敏感性的作用还没有研究报道。

　　营养所郭非凡组研究人员于俊杰等通过从影响丝氨酸合成的酶PSAT1入手系统研究了PSAT1在调节胰岛素敏感性中的作用和机制。研究发现在胰岛素抵抗小鼠（包括db/db及高脂诱导的胰岛素抵抗小鼠模型）中，肝脏PSAT1表达显著降低，而过表达PSAT1可以显著提高抵抗小鼠的胰岛素敏感性，进一步研究发现PSAT1通过TRB3来调节胰岛素敏感性，而丝氨酸介导了PSAT1对TRB3的调节，胰岛素抵抗小鼠肝脏中丝氨酸水平显著降低，揭示了丝氨酸对胰岛素敏感性的调节作用。

　　该研究证实了PSAT1在调节肝脏胰岛素敏感性方面的重要作用，提出丝氨酸可能作为一种非必需氨基酸对胰岛素敏感性具有调节作用，这为全面理解胰岛素敏感性的调控关系提供了理论依据，也加深了人们对2型糖尿病及相关代谢性疾病发病机制的理解。

　　该项研究得到国家自然科学基金、上海科教委以及中科院等科研基金的支持。

原文摘要：

Hepatic phosphoserine aminotransferase 1 (PSAT1) regulates insulin sensitivity in mice via tribbles homolog 3 (TRB3)
Phosphoserine aminotransferase 1（PSAT1）is an enzyme participating in serine synthesis. A role of PSAT1 in the regulation of insulin sensitivity, however, is unknown. Here, we showed that hepatic PSAT1 expression and liver serine levels are reduced in genetically engineered leptin receptor-deficient (db/db) mice and high-fat diet (HFD)-induced diabetic mice. Additionally, over-expression of PSAT1 by adenovirus expressing PSAT1 (Ad-PSAT1) improved insulin signaling and insulin sensitivity in vitro and in vivo under normal conditions. Opposite effects were observed when PSAT1 was knocked down by adenovirus expressing small hairpin RNA specific for PSAT1 (Ad-shPSAT1). Importantly, over-expression of PSAT1 also significantly ameliorated insulin resistance in diabetic mice. In addition, PSAT1 inhibited the expression of hepatic tribbles homolog 3 (TRB3) in vitro and in vivo, and Ad-shTRB3-mediated inhibition of TRB3 reversed the attenuated insulin sensitivity in Ad-shPSAT1 mice. Interestingly, we found that serine mediates PSAT1 regulation of TRB3 expression and insulin signaling in vitro. These results identify a novel function for hepatic PSAT1 in regulating insulin sensitivity and provide important insights in targeting PSAT1 for treating insulin resistance and type 2 diabetes. Our results also suggest that non-essential amino acid serine may play an important role in regulating insulin sensitivity.