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

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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.