Spexin通过抑制胆固醇7-α-羟化酶（CYP7A1）的表达调控胆汁酸合成的作用机制研究

胆汁酸是一种重要的内源性代谢物，其代谢异常导致多种肝胆胃肠疾病的发生。我们前期研究发现一种新型肽spexin能显著降低大鼠血清及肝脏中牛磺酸结合型胆汁酸的含量，并抑制胆汁酸合成酶——胆固醇7-α-羟化酶(CYP7A1)的表达。此外，spexin显著上调小鼠肝脏中SHP、c-fos和c-Jun等CYP7A1转录抑制因子的表达。由此推测，spexin很有可能通过抑制胆汁酸合成而影响胆汁酸肝肠循环。本项目将通过体外细胞模型研究spexin受体激活后CYP7A1的基因及蛋白水平的变化，并结合相关信号转导通路以及转录因子调控来探讨其机制。然后，在小鼠模型中系统检测spexin给药后胆汁酸肝肠循环的变化，以及调控胆汁酸合成、结合、重吸收和负反馈的基因的表达，并考察小鼠肝功能指标和肝脏病理变化。此研究为阐明spexin在肝肠循环中的生理功能提供有力证据，并为研究相关疾病中胆汁酸代谢紊乱机制提供理论基础。

Bile acids (BAs) are major components of bile, which is essential for digestion and absorption of fats and fat-soluble vitamins. The disruption of BAs is generally considered as an aetiological factor to hepatobiliary or gastrointestinal diseases. Our preliminary study found that a novel endogenous peptide, spexin significantly reduced the levels of taurine-conjugated BAs in serum and hepatic tissues, also down-regulated the expression of hepatic cholesterol 7-alpha- hydroxylase (CYP7A1) in rats. Moreover, expressions of small heterodimer partner (SHP), c-fos and c-Jun responsible for down-regulation of CYP7A1 transcription were found remarkably elevated in spexin-injected mice. These results suggest that spexin affects BA synthesis and metabolism. To prove the hypothesis, underlying mechanism of spexin on regulation of CYP7A1 gene/protein expression and BA synthesis will be firstly investigated in vitro. Secondly, BA profiles and proteins involved in enterhepatic circulation will be investigated in mice subject to spexin treatment. Thirdly, serum index related to hepatic functions together with hepatic pathology will be evaluated in spexin-treated mice. The proposed study will clarify the physiological functions of spexin on BA modulation throughout enterohepatic circulation, which benefits understanding pathogeneses of multiple diseases with phenotypes of BA disruption.