中药复方贞术调脂胶囊通过调节A-FABP介导的脂肪-卵巢对话干预多囊卵巢综合征的作用及机理研究

Polycystic ovary syndrome (PCOS) has been well documented to be closely associated with obesity and its related metabolic disorders. Metabolic inflammation has been indicated to play a potentially crucial role in the pathogenesis of PCOS. In the pilot study, we found that circulating levels of adipocyte fatty acid binding protein (A-FABP) were significantly elevated in patients with PCOS. In addition, gene expression of A-FABP was notably up-regulated in ovary tissue from mouse model of PCOS. Ex-vivo incubation of pre-adipocyte 3T3-L1 with serum containing Chinese Medicine Fu-Fang-Zhen-Zhu-Tiao-Zhi recipe (FTZ) significantly suppressed the release of A-FABP. In light of these preliminary results, we hypothesize that A-FABP can potentiate the pathogenesis of PCOS through promoting the infiltration of macrophages in ovary tissue and enhancing the production of pro-inflammatory factors, thereby increasing the infiltration of other inflammatory cells and resulting in the development of PCOS. We further hypothesize that Chinese Medicine FTZ can attenuate PCOS through modulating A-FABP-mediated crosstalk between fat and ovary tissue. To test the hypothesis, three independent studies will be performed, including “loss-of-function” study using A-FABP knockout mice, recombinant A-FABP protein-mediated “gain-of-function” study, and the treatment in mice with FTZ or A-FABP inhibitor. It is expected that the findings will be of significant importance in the delineation of the molecular mechanisms underlying the pathogenesis of PCOS and the development of new drugs targeting A-FABP.

多囊卵巢综合征(PCOS)是与肥胖及代谢性炎症密切相关的内分泌紊乱症候群。本课题组前期研究发现，PCOS患者外周血中脂肪细胞型脂肪酸结合蛋白(A-FABP)水平显著升高；A-FABP在PCOS小鼠模型卵巢中表达水平显著升高；中药复方贞术调脂胶囊体外孵育可显著抑制前脂细胞3T3-L1中A-FABP的释放。基于此，本课题提出研究假设“A-FABP可促进卵巢组织的巨噬细胞浸润，并导致促炎性因子的生成增多，进而导致多种炎症细胞的卵巢组织浸润，诱发PCOS的发病；中药复方贞术调脂胶囊可通过抑制A-FABP而改善PCOS”。为验证该研究假设，本项目分为三个部分，包括A-FABP敲除小鼠卵巢功能表型鉴定、重组小鼠A-FABP蛋白持续灌注，及中药复方贞术调脂胶囊及A-FABP药物性抑制剂干预实验。研究结果将对于揭示PCOS的发病机制以及以A-FABP靶点的药物研发具有重要科学意义。

多囊卵巢综合征（PCOS）是女性最常见的内分泌、代谢和生殖异常综合征，对患者身心健康产生巨大影响。但目前PCOS的发病机制尚不明确，且治疗策略和药物非常有限。因此，对PCOS的关键发病机制进行深入研究、发现新的干预策略和探索中医药对于PCOS的干预作用具有重要科学意义。.本课题着眼于卵巢颗粒细胞来源的分子A-FABP，通过建立小鼠PCOS模型和A-FABP敲除小鼠的系统表型分析、中药复方FTZ干预效果评价等策略，获得以下重要科学发现：（一）、以来曲唑（LET）联合高脂饮食方案诱导PCOS模型，并进行生殖代谢表型分析及A-FABP水平检测，发现PCOS小鼠卵巢A-FABP表达明显升高，主要来源定位于卵巢颗粒细胞。（二）、基因敲除诱导的A-FABP缺失可显著改善小鼠PCOS相关的卵巢功能障碍和不孕症。（三）、以A-FABP药物抑制剂BMS309403（BMS）对小鼠PCOS具有显著干预和治疗作用。（四）、中药复方FTZ可显著改善PCOS小鼠卵巢病理改变、发情周期紊乱，可改善内分泌紊乱、葡萄糖耐受及脂质代谢情况。.本课题研究结果具有以下科学意义：(1). 本课题结果说明A-FABP在PCOS发病中发挥重要病理生理学功能，对于阐明PCOS的关键病理生理机制具有重要科学意义。(2). 本课题结果提示A-FABP是针对PCOS进行药物研发的潜在靶点。(3). 本研究结果显示中药复方贞术调脂胶囊（FTZ）可显著改善PCOS，提示中药复方FTZ可作为治疗PCOS的潜在中药，凸显出中药复方制剂治疗致病机制复杂的临床证候的良好应用前景。.本课题主要科学发现以原创性研究论文发表于Journal of Ethnopharmacology (Ying Xu, et al. Traditional Chinese Medicine formula FTZ protects against polycystic ovary syndrome through modulating adiponectin-mediated fat-ovary crosstalk in mice, Journal of Ethnopharmacology, 2021. https://doi.org/10.1016/j.jep.2020.113587)。依托本项目，培养硕士研究生2名（郭倩愉、唐嘉玲，广东药科大学）