肝X受体（LXR）在多囊卵巢综合征脂代谢紊乱发生中的作用

Dyslipidemia is common in women with polycystic ovary syndrome (PCOS). Obesity, insulin resistance and androgen excess are important factors that can influence lipid metabolism in women with PCOS. LXRs play a key role in lipogenesis and glucose homeostasis. In addition, LXRs are essential regulators of cholesterol homeostasis and as the precursor of androgen, cholesterol can affect the level of androgen. Our preliminary data showed the high expression of LXRalpha in theca cells, where androgen is produced. Thus the aim of the project is to study the role for LXRs in lipid metabolism in PCOS. LXRs likely regulate lipid metabolism in PCOS through two different pathways, namely regulation of glucose and lipid metabolism in the liver and management of androgen synthesis in the ovaries. In the first part of the project, we will generate PCOS mouse model and detect the expression of LXRs in the liver and ovaries of PCOS mice. By using LXR agonists and generating PCOS mice in the context of LXR gene deficiency, we will show how altered LXR levels influence lipid metabolism in PCOS mice. In the second part of the project, the effects of LXRs and androgen on hepatic glucose and lipid metabolism and the regulation of ovarian androgen production by LXRs will be investigated at the cellular level in vitro. The accomplishment of this project will help to illustrate the role for LXRs in the genesis of dyslipidemia in PCOS and provide the possible therapeutic target and experimental evidence for the treatment of dyslipidemia in women with PCOS.

脂代谢异常是多囊卵巢综合征（PCOS）患者常见的代谢紊乱。肥胖、胰岛素抵抗、和雄激素过多是影响PCOS脂代谢的重要因素。LXRs在调节脂肪生成和糖代谢方面起关键作用，同时，LXRs对维持胆固醇稳态有重要意义，而胆固醇作为雄激素的前体，直接影响雄激素水平。我们的前期结果表明LXRalpha高表达于合成雄激素的卵泡膜细胞。本课题旨在研究LXRs通过调节肝脏糖脂代谢和卵巢雄激素合成两条途径，在PCOS脂代谢中的作用及机制。研究内容一将诱导产生PCOS小鼠，检测LXRs在PCOS小鼠肝脏和卵巢中的表达，并通过应用LXRs激动剂和LXR基因敲除小鼠，阐明LXRs水平改变对PCOS脂代谢的影响；研究内容二将在细胞水平研究LXRs和雄激素对肝脏糖脂代谢和LXRs对卵巢雄激素合成的影响。本课题的开展将有助于阐明LXRs在PCOS脂代谢紊乱发生中的作用，从而为PCOS脂代谢紊乱的治疗提供可能靶点和实验依据。

脂代谢异常是多囊卵巢综合征（PCOS）患者常见的代谢紊乱。LXRs在调节脂肪生成和糖代谢方面起关键作用，同时，LXRs对维持胆固醇稳态有重要意义，而胆固醇作为雄激素的前体，直接影响雄激素水平。本研究拟通过改变LXRs的表达，阐明LXRs水平改变对PCOS脂代谢的影响。在本课题的资助下，我们共发表了5篇SCI论文，2篇中文核心期刊。其中一篇研究论文发表在Biology of Reproduction，在这部分工作中我们发现高脂饮食可使DHEA诱导的多囊卵巢综合征小鼠表现出多方面的代谢紊乱症状。我们的工作一方面为PCOS代谢紊乱的病理机制研究，特别是PCOS患者高发脂肪肝的病理机制研究提供了一个很好的研究工具，另一方面也提示在青春期前后，如果饮食不当会加重PCOS的表型，特别是代谢紊乱表型。该论文被英国医学与生物学论文评价和检索系统Faculty of 1000收录，并推荐为杰出论文。我们在另一篇研究论文中报道：DHEA或DHEA+60%HFD诱导的PCOS小鼠有类抑郁行为，该行为与脑中单胺神经递质或其代谢产物的减少有关。此外，我们发现DHEA和DHEA+HFD诱导的两种PCOS小鼠的肝脏中，LXRbeta的表达显著高于对照组；LXR 激动剂T0901317加重了PCOS小鼠脂代谢紊乱，并对高雄激素血症、性周期紊乱和多囊卵巢无明显改善；LXRalpha和LXRbeta基因敲除小鼠诱导的PCOS小鼠与野生型小鼠相比，多方面的检测结果提示LXRbeta可能在PCOS的病理机制中具有比LXRalpha更重要的作用。