Previous Research
The following research has been funded by the PBC Foundation.
The PXR receptor and Primary Biliary Cirrhosis treatment
Dr Matthew Wright
Department of Molecular and Cell Biology
Institute of Medical Sciences
University of Aberdeen
Scotland
The cause or causes of PBC are unknown but it appears to be dependent on the immune system mistakenly attacking the cells in the bile ducts. This makes finding a cure for PBC very difficult because we cannot live without our immune system. So what else can we do in the meantime? We could try to reduce the severity of the disease so that the symptoms and long term effects of PBC are less devastating.
The symptoms of PBC disease can be distressing and significantly impair the quality of life for sufferers. Many of the symptoms of PBC can be placed either directly or indirectly at the door of bile acids and their accumulation within the body. This is because their progress to the gall bladder and intestines is impaired by a loss in bile duct integrity. Bile acts like washing-up liquid on fat in that it helps to break-up fat in the gut so that it can be more readily digested and absorbed. But the membranes of all the cells within the body are also made of fat. A build up of bile acid in tissues such as the liver will therefore have the effect of breaking them up also, and damaging the tissue. A possible solution to this problem is to encourage any additional bile acid that may build up to leave the body by a route in addition to the bile duct, i.e. via the kidneys and into the urine. To do this, we need to metabolise the bile acid to make it more water soluble. (Picture of the Lab Staff at Aberdeen).
One treatment for PBC that has some benefits is the administration of the bile acid urso. It has seemed odd however, that a solution to high levels of bile acid within the liver might be helped by taking even more bile acid! But it has recently been realised that urso is one of the bile acids that binds to the PXR receptor. This receptor controls the levels of an enzyme in the liver that is able to make bile acids more water-soluble.
Would we see better results in PBC if drugs that bind to the PXR receptor - but are not bile acids - are used instead of Urso? We will examine this question in a model of the disease, to see if the PXR receptor can really provide the key to improvements in the quality of life for PBC sufferers. There is good reason to be optimistic. The problem with PBC is that chronic liver damage caused by the block in bile release into the bile duct can result over time to liver damage, liver fibrosis and cirrhosis. Complementary work in our lab indicates that cells responsible for liver fibrosis in the liver also contain the PXR receptor. In these cells, drugs that bind to the PXR stop the cells causing fibrosis.
Therefore, we may be able to reduce the damaging effects of PBC by increasing bile acid metabolism to less toxic products that can be eliminated from the body more readily and by reducing the chances that fibrosis will develop if bile acid levels do increase to damaging levels. It is hoped that the combined effect of these outcomes will make living with PBC a little easier and may delay the need for more intensive treatments such as liver transplantation.