雌激素及胆汁酸基于cAMP-AMPK-HNF1α-FXR通路调控胆汁淤积的作用机制研究

Cholestasis, as a common liver damage symptom with high morbidity in clinic, is often neglected in the early stage due to the lack of biomarkers and appropriate therapeutics. Meanwhile, it can induce many severe diseases, like hepatocellular carcinoma and cholangiocarcinoma. Many factors, such as drugs, hepatitis and sex hormone, had been documented as risk factors of cholestasis, while the pathogenesis of this disease is still unclear. We preliminarily identified the main endpoint of estrogen-induced liver toxicity and hepatocyte polarity structure impairment in rats, and established bridges between AMPK, FXR and Estrogen-induced cholestasis. Based on these findings, to determine the possible molecular mechanism of cholestasis, we intend to investigate the mechanism of estrogen-induced cholestasis via cAMP-AMPK-HNF1α-FXR pathway; determine the interaction between AMPK and FXR; explore regulatory mechanism of AMPK and FXR in cholestasis; evaluate the role of AMPK and FXR as therapeutic targets in cholestasis, and further investigate potential prognostic effects of different bile acids in cholestasis. The results demonstrate the pathogenesis of estrogen-induced cholestasis and provide theoretical basis for the development of clinical therapy.

胆汁淤积是临床高发的肝损伤症状，早期易被忽视，该疾病缺少生物标志物和良好的治疗药物，可诱发肝癌、胆管癌等多种严重疾病。药物、肝炎、性激素等多种因素均可引起胆汁淤积，但其发病机制尚不明确。课题组已明确了雌激素致大鼠胆汁淤积性肝损伤的主要终点及肝细胞极性结构改变，发现AMPK、核受体FXR与雌激素所致的胆汁淤积密切相关。在此基础上，继续考察雌激素经cAMP-AMPK-HNF1α-FXR通路诱发胆汁淤积的作用机制，阐明AMPK、FXR两者之间的相互作用，探讨胆汁淤积时AMPK、FXR的调控机制，评估AMPK和FXR作为治疗靶点在胆汁淤积中的作用，进一步考察不同胆汁酸对于肝脏胆汁淤积的预后影响。课题的研究结果可以阐明雌激素所致的胆汁淤积发病机制，为胆汁淤积临床治疗药物的研究开发提供理论依据，项目研究对于揭示其他因素所致胆汁淤积的发病机制研究具有重要的指导意义。

胆汁淤积是临床高发的肝脏疾病，早期易被忽视，该疾病缺少生物标志物和良好的治疗药物，可诱发肝癌、胆管癌等多种严重疾病。药物、肝炎、性激素等多种因素均可引起胆汁淤积，但其发病机制尚不明确。.本课题发现雌激素（EE）诱发的胆汁淤积性肝损伤伴随着胆汁酸循环池中胆汁酸的稳态失衡，而这一现象可能与肝细胞极性的改变有关。研究结果表明EE可以通过激活肝实质细胞的G蛋白偶联受体（GRP30）以及环腺苷酸（cAMP）-细胞外调节蛋白激酶（ERK）-肝激酶B1（LKB1）信号通路，诱导AMP活化蛋白激酶（AMPK）磷酸化水平升高，促进AMPKα1亚基入核，从而抑制核受体FXR的表达以及其下游胆汁酸转运体靶点，导致肝细胞内胆汁酸稳态失衡。.临床治疗胆汁淤积以及胆道疾病的两种胆汁酸鹅去氧胆酸（CDCA）和熊去氧胆酸（UDCA）可以通过激酶A（PKA）-AMPK通路恢复EE介导的法尼醇X受体（FXR）及其下游胆汁酸转运体的抑制作用，缓解EE导致的胆汁淤积现象，且这两种胆汁酸的牛磺酸及甘氨酸的代谢型都具有这一作用，但脱氧胆酸（DCA）并不具有这一作用，且会加重EE介导的胆汁淤积现象。.综上，抑制AMPK激酶的过度磷酸化、激活FXR核受体和PKA激酶均会改善EE造成的胆汁淤积，提示这些靶点均是胆汁淤积治疗的潜在靶点。研究结果为探索胆汁淤积疾病的发病机制、寻找新型治疗方案提供了理论依据。