硫辛酸合成关键酶HTD2在2型糖尿病中的作用及机制研究

Insulin resistance (IR) is the common pathogenesis of metabolic syndrome such as Type 2 Diabetes. Current opinions suggest that mitochondrial dysfunction is a major etiological factor in IR. α-Lipoic acid (α-LA) is a natural antioxidant, which has a critical role in mitochondrial function and energy metabolism because of its function as an essential cofactor of pyruvate dehydrogenase and α-ketoacid dehydrogenases. Mitochondrial 3-hydroxyacyl thioester dehydratase 2 (HTD2), a highly conserved enzyme in eukaryotes, is a member of the mitochondrial fatty acid synthase II that is involved in the synthesis of octanoic acid, the precursor of α-LA, and longer chain fatty acids. According to our preliminary data, HTD2 is associated with metabolic syndrome. Deficiency of HTD2 leads to mitochondrial dysfunction, increased level of reactive oxygen species, and declined insulin sensitivity. Therefore, we propose that HTD2 may play an important role in metabolic syndrome progression through regulation of α-LA synthesis to affect mitochondrial function, leading to the development of type 2 diabetes. This proposal will focus on the role of HTD2 in IR with cellular and animal models using knockout and over expression techniques. The research will provide evidence of the function and mechanism of HTD2 in IR and new target and strategy for prevention and treatment of type 2 diabetes.

胰岛素抵抗是2型糖尿病的核心病理基础，而活性氧增多所致的线粒体功能障碍是推动胰岛素抵抗的重要因素之一。作为天然抗氧化剂和丙酮酸脱氢酶及α-酮戊二酸脱氢酶的辅酶，硫辛酸在清除自由基、维持线粒体功能中发挥重要作用。线粒体脂肪酸合成途径FASII通路可以合成硫辛酸前体和其它长链脂肪酸，线粒体3-羟烷基硫酯脱水酶2（HTD2）是FASII通路中的一员，在真核生物中高度保守。我们前期探索发现，HTD2与2型糖尿病紧密相关：HTD2敲低引起线粒体功能障碍、活性氧升高及胰岛素敏感性降低，提示HTD2可能通过影响硫辛酸合成来调控线粒体功能进而参与2型糖尿病发生发展。本课题拟通过胰岛素抵抗的细胞和动物模型结合基因操作手段对HTD2的生物学功能进行深入探讨，明确其在胰岛素抵抗中的作用机制，并为2型糖尿病的防治提供新的靶点或策略。

胰岛素抵抗是2型糖尿病的核心病理基础，而活性氧增多所致的线粒体功能障碍是推动胰岛素抵抗的重要因素之一。作为天然抗氧化剂和丙酮酸脱氢酶及α-酮戊二酸脱氢酶的辅酶，硫辛酸在清除自由基、维持线粒体功能中发挥重要作用。线粒体脂肪酸合成途径FASII通路可以合成硫辛酸前体和其它长链脂肪酸，线粒体3-羟烷基硫酯脱水酶2（HTD2）是FASII通路中的一员，在真核生物中高度保守。我们研究发现，肥胖及糖尿病模型小鼠脂肪组织中Htd2基因表达显著下降，FASII通路受到抑制；脂肪细胞中Htd2缺失诱发线粒体功能紊乱，导致细胞胰岛素抵抗；α-LA的补充可以改善Htd2缺失所引起的线粒体功能障碍以及细胞胰岛素抵抗；小鼠脂肪组织中Htd2的缺失导致了小鼠寿命缩短及运动功能障碍。我们发现HTD2与代谢综合征的发病紧密相关，它的表达降低能够引起线粒体功能障碍、活性氧升高以及细胞对胰岛素敏感性下降。同时我们认为HTD2可能通过α-LA合成的改变来影响线粒体氧化应激水平，从而参与胰岛素敏感性调控和代谢综合征的发生发展。