mtKAS调节细胞硫辛酸水平及参与胰岛素抵抗的作用机制

Alpha-lipoic acid (α-LA)，an important coenzyme in glucose metabolism, is one of the "mitochondria nutrients" closely involved in mitochondrial function and insulin signaling. However, how cellular α-LA level is regulated remains largely unknown. Recently, our pilot study suggests that the α-LA synthetase, Mitochondrial β-ketoacyl-acyl carrier protein synthase (mtKAS), decreased significantly under the condition of insulin resistance, and intracellular mtKAS knock down leads to mitochondrial dysfunction, thus promoting the insulin resistance. We suppose that mtKAS determines α-LA level and impacts the progression of insulin resistance. In the present study, we will firstly examine the expression of mtKAS and α-LA levels of insulin sensitive tissues in animal models, to characterize the mtKAS expression under the condition of insulin resistance; Then to explore the role of mtKAS in regulating mitochondrial function and formation of insulin resistance with cell and animal models being of mtKAS knockout or over expression; Finally, to explore mechanism underlying mtKAS expression during the progression of insulin resistance. This study will reveal for the first time cellular LA homeostasis, and elucidate how the mtKAS be involved in the occurrence of insulin resistance.

硫辛酸是线粒体内若干关键代谢酶的辅酶，也是研究团队提出的 “线粒体营养素”之一，与线粒体功能及胰岛素信号密切关联。但长期以来，细胞内硫辛酸水平的调节机制并未明确。我们近期发现，线粒体β-酮脂酰ACP合成酶（mtKAS）在胰岛素抵抗条件下显著抑制，降低细胞内mtKAS引起硫辛酸水平及胰岛素敏感性减低，提示mtKAS通过调节硫辛酸水平，参与胰岛素抵抗形成。为明确mtKAS对硫辛酸水平的调节功能，揭示其参与胰岛素抵抗的分子机制，本研究将首先采用多种胰岛素抵抗模型，检测胰岛素敏感组织中mtKAS的表达及硫辛酸水平，确认其表达特征与功能；进而采用mtKAS敲除或过表达手段，研究mtKAS调节线粒体功能和对胰岛素信号的影响；最终通过代谢因素调控mtKAS表达与活性的研究，明确其参与胰岛素抵抗的分子机制。本研究将揭示细胞硫辛酸水平的关键调节分子，阐明mtKAS参与胰岛素抵抗的新机制。

真核细胞中有两条脂肪酸合成途径，分别是细胞质中脂肪酸合成酶（FASN)途径和线粒体脂肪酸合成途径(mtFAS)。FASN途径已有较清晰的研究阐释，但mtFAS途径介导的细胞功能基本未知。mtFAS途径中，有研究认为线粒体β-酮脂酰ACP合成酶（mtKAS）参与体内重要辅酶硫辛酸的合成，我们发现，mtKAS对细胞内结合型硫辛酸几无影响，但参与肌肉细胞代谢和细胞增殖调节。在地塞米松诱导的肌萎缩模型中mtKAS显著升高，肌萎缩模型中敲低mtKAS能够显著降低细胞凋亡，增加抗氧化水平，抑制肌萎缩发生。相反，mtKAS在结肠癌细胞中显著降低，在结肠癌中敲低mtKAS能够显著促进结肠癌细胞的生长。进一步研究发现，mtKAS可能通过细胞因子代谢途径调控细胞生长，且 miR-4659a-3p是代谢调控的关键分子。本研究明确mtKAS对肌细胞及肿瘤细胞生长具有重要调控作用，是肌萎缩和结肠癌发生中重要的防治靶点。