游离脂肪酸通过抑制睾丸间质细胞StAR减少睾酮合成及机制

Men often have increased free fat acids(FFA), reduced testosterone in serum and sexual dysfunction.Testosterone is mainly synthesized by Leydig cells, and StAR is the key molecular in the rate-limiting step.In epidemiological studies, we have found that testosterone in serum was negatively correlated with triglycerides level in men. Besides, in rats fed with high-fat diet, the expression of StAR was decreased in Leydig cells.Activation of mitochondria oxidative stress (OS) pathway is an important mechanism in FFA induced cell injury. However,there is few studies reporting the injury to Leydig cells and the mechanism is not clear. We will perform research in vitro and in vivo on animal, cell, and molecular levels. In vivo experiments, the change of StAR expression, testosterone synthesis, mitochondria OS and molecules in NF-kB/SF-1 pathway in Leydig cells and the effects of antioxidants intervention in mice will be investigated. In vitro experiments, the impact of mitochondria OS and NF-kB on StAR expression and testosterone synthesis will be studied by anti-OS and inhibiting NF-κB expression. Based on the research above, we explore a novel mechanism of FFA reducing testosterone synthesis by inhibiting StAR expression in Leydig cells, hoping to provide a new approach for treatment of Leydig cell dysfunction induced by FFA.

肥胖男性常伴有血游离脂肪酸（FFA）升高、睾酮水平降低及性功能减退。睾酮主要由睾丸Leydig细胞合成，StAR为其限速步骤中的关键分子。本课题组流行病学调查显示男性血甘油三脂与睾酮呈负相关；高脂喂养大鼠的Leydig细胞StAR表达降低。线粒体氧化应激(OS)通路激活是FFA致组织细胞损害的重要机制，而FFA对Leydig细胞作用国内外少见报道且机制不清。本项目拟从动物、细胞、分子三个水平，采用体内和体外实验相结合的研究方法，观察小鼠体内FFA对Leydig细胞合成睾酮影响、StAR、线粒体OS及相关通路NF-κB/SF-1分子的改变及抗氧化剂干预的作用；并在细胞中分别通过抗线粒体OS、抑制NF-κB表达，观察对Leydig细胞StAR表达和睾酮合成的影响，旨在探讨FFA通过抑制StAR表达减少睾酮合成的机制，为FFA引起Leydig细胞功能障碍寻找新的治疗靶点。

如今，肥胖男性常伴有血游离脂肪酸（FFA）升高、睾酮水平降低及性功能减退。睾酮主要由睾丸Leydig细胞合成，StAR为其限速步骤中的关键分子。本课题组前期研究发现男性血甘油三脂与睾酮呈负相关，而FFA引起Leydig细胞睾酮合成降低的具体机制尚不清楚。本项目主要采用了体内与体外相互验证方法，以睾丸Leydig细胞睾酮合成的关键蛋白-StAR为切入点，针对FFA抑制睾酮合成的相关分子机制作了一系列研究，主要结果如下：①证实FFA刺激可上调睾丸Leydig细胞内线粒体CypD的表达，影响线粒体氧化呼吸链的功能，最终导致线粒体结构和功能异常，抑制睾酮合成的关键蛋白StAR 的表达，睾酮合成减少；②通过高脂饮食喂养构建的小鼠模型进一步得到验证：高脂饮食通过上调睾丸Leydig细胞线粒体CypD，造成雄性小鼠的脂代谢紊乱，睾丸内氧化应激增加，抑制StAR的表达，导致睾酮合成减少，生育能力降低。③高胆固醇饮食同样造成小鼠血脂异常，睾丸脂质沉积，进而导致内质网应激被激活，睾丸功能障碍，睾酮合成降低。④脂肪组织参与调控睾酮代谢，影响男性性腺功能，二甲双胍可通过调控ROS-NF-κB通路，改善脂毒性损伤的男性生育能力。本研究阐明了FFA抑制睾丸Leydig细胞睾酮合成的相关分子机制，为干预FFA引起 Leydig细胞功能障碍提供了科学依据。