MTA3参与Ⅱ型糖尿病并发睾丸间质细胞睾酮合成障碍的作用机制

Ⅱ型糖尿病男性患者常并发睾丸间质细胞（LCs）睾酮合成障碍，严重影响生活质量和生育。肿瘤转移相关蛋白（MTA）是一类通过募集组蛋白去乙酰化酶发挥重要调节作用的转录因子。我们最新研究显示，MTA3在睾丸主要表达于LCs，它是LCs激素合成的必需条件；小鼠Ⅱ型糖尿病模型中，睾丸MTA3表达量与睾酮水平呈正相关；在LCs细胞，MTA3过表达可部分逆转高胰岛素水平对睾酮合成的抑制作用。此外，在MTA3稳定敲除的LCs细胞，Adiponectin表达异常升高。据此推测，MTA3/Adiponectin信号可能参与了Ⅱ型糖尿病并发睾酮合成障碍的病理发生。本项目拟深入研究MTA3在睾酮合成过程中的作用细节，重点分析Ⅱ型糖尿病并发睾酮合成障碍过程中MTA3与Adiponectin的相互作用关系并筛选MTA3下游作用信号。本研究将为理解Ⅱ型糖尿病并发性腺功能低下症的复杂发病机理提供重要新线索。

Disruption of the local pathways in Leydig cells (LCs) by diverse pathological conditions such as type 2 diabetes mellitus (T2DM) is frequently associated with androgen deficiency-induced sexual dysfunction and male infertility. Metastasis-associated proteins (MTA) are involved in the transcriptional regulation of key molecules by modifying the deacetylation status of crucial target genes via recruitment of histone deacetylases. We have recently found that in testis, MTA3 was mainly expressed in LCs and was indispensable for testicular steroidogenesis. Attenuated Mta3 expression positively correlated to the deregulated level of serum testosterone in murine T2DM model. Moreover, MTA3 overexpression could partially reverse the deleterious effect of hyperinsulinemia on androgen production in LCs. Additionally, adiponectin of LCs was found to be abnormally upregulated in the presence of MTA1 ablation. Taken together, we reason that MTA3/Adiponectin cascade may directly participate in the androgen deficiency under T2DM status. The present study is therefore designed to further illustrate the functional details of MTA1 during testicular steroidogenesis, with emphasis on the potential interaction between MTA3 and Adiponectin signaling in the disruption of testosterone synthesis by T2DM. Finally, we will try to identify the potential downstream signaling of MTA1 during the above-mentioned complicated pathogenesis. Our systematic analysis should provide important novel evidence for understanding the complicated pathogenesis of T2DM complicated with hypogonadism.