Molecular mechanisms of feed-forward regulation of bile acid detoxification and elimination in cholestasis

胆汁流动受阻的肝脏疾病（胆汁淤积性肝病）可导致肝衰竭、肝硬化以及生活质量下降。患者患有严重的瘙痒，这可能证明难以控制。据认为，胆汁流动受阻的这些不良影响可能是由于体内一种称为胆汁酸的成分或胆汁的滞留。胆汁酸是由胆固醇形成的洗涤剂样化合物。一些胆汁酸是高毒性的，如果它们的浓度过高，会导致肝脏内细胞的死亡。有证据表明，在胆汁淤积性肝病中，身体有控制机制来试图对抗胆汁酸水平的上升。这些控制机制是复杂的，包括来自细胞色素P450家族的酶以及几种专门的转运分子。在胆汁淤积中，这些机制促进胆汁酸通过尿液的清除，以及将毒性很强的胆汁酸转化为毒性较低的形式。目前的项目建立在我们小组过去几年中关于细胞色素P450酶调节的发现的基础上，包括对某些药物增加CYP3A产量的方式的深入了解。我们打算详细确定如何防御机制对有毒胆汁酸从事。特别是，我们希望确定受体分子，“感觉”胆汁淤积性肝病中发生的胆汁酸水平上升。对这些问题的理解将使我们能够更好地管理这些疾病的专利，并开发治疗胆汁淤积性疾病的新策略，例如，开发可以影响肝脏和其他器官中胆汁酸解毒的新药。

Liver diseases in which there is obstruction to bile flow (cholestatic liver diseases) can lead to liver failure, liver cirrhosis as well as a diminished quality of life. Patients suffer from severe itching which may prove difficult to control. It is thought that may of these adverse effects of obstructed bile flow are due to the retention of a component or bile, called bile acids, within the body. Bile acids are detergent-like compounds formed from cholesterol. Some bile acids are highly toxic and cause the death of cells within the liver if their concentration becomes too high. Evidence has emerged that the body has control mechanisms to try and combat rising levels of bile acids in cholestatic liver diseases. These control mechanisms are complex and include enzymes from the cytochrome P450 family as well as several specialized transport molecules. In cholestasis these mechanisms promote the removal of bile acids through the urine as well as converting very toxic bile acids to less toxic forms. The present projects builds on discoveries concerning the regulation of cytochrome P450 enzymes made by our group over the last few years, including an in-depth understanding of the way the production of CYP3As is increased by some drugs. We intend to determine in detail how defense mechanisms against toxic bile acids are engaged. In particular, we wish to identify the receptor molecules that 'sense' the rising levels of bile acids that occur in cholestatic liver diseases. An understanding of these issues will allow us to better manage patents with these diseases and develop new strategies for treating cholestatic disorders, for example, development of novel drugs that can influence bile acid detoxification in the liver and other organs.