April 2012

From the inside out

New study gives clues on how the only FDA-approved drug to treat primary biliary cirrhosis works in the liver



jlr_coverA small amount of ursodeoxycholic acid, also known as UDCA or ursodiol, has been a component in Chinese traditional medicine treatment for liver disorders for centuries. In the Western world, UDCA is the only approved drug to treat primary biliary cirrhosis, an autoimmune disorder characterized by progressive damage to the bile ducts within the liver, causing a buildup of cholesterol in the liver and subsequent liver damage. Without treatment, most patients with this condition will need a liver transplant later in life, and a quarter of patients who have had the condition for more than 10 years will suffer liver failure. UDCA also has been shown to prevent the progression of colorectal cancer and the recurrence of colonic dysplasia, the development of precancerous, abnormal cells in the colon. But the mechanism by which UCDA counteracts these liver problems hasn’t been completely elucidated.

In their paper entitled “Ursodeoxycholic acid binds ileal bile acid binding protein,” to be published in the April issue of the Journal of Lipid Research, Changming Fang and colleagues at the Cancer Research Center at the Sanford-Burnham Medical Research Institute in La Jolla, Calif., set out to determine if ileal bile acid binding protein, or IBABP, a cytosolic protein believed to be involved in the absorption of bile acids associated with the processing of dietary fat, is involved with UCDA’s activity in the human body (1).

Major human bile acids bind to two sites on IBABP and act in a cooperative manner in healthy individuals. In contrast, they found by tryptophan fluorescence spectroscopy that UCDA only binds to a single site. Further, when IBABP was saturated with UDCA, the affinity of IBABP for major human bile acids increased two- to five-fold, and UDCA was shown to bind cooperatively with a major human bile acid bound to the other binding site just as two bile acids normally do while sitting in these binding sites.

IBABP also associates with farnesoid X receptor alpha, or FXRα, and had been assumed as a mediator of this receptor’s activity. While it is still not clear how this mediation occurs, Caco-2 cell culture results from this study indicate IBABP is involved in UDCA’s effect to increase the activation of this receptor. Further research is needed to determine IBABP’s precise mechanism of action.

This article highlights the importance of considering IBABP’s activity and role in UDCA’s potential benefits in patients with liver damage. UDCA increases the binding of major human bile acids; this decreases the number of free bile acids in cytosol, reducing stress on the gastrointestinal system and preventing bile acid-induced mutations and the development of bile acid resistance seen in colorectal cancer. The authors suggest that, based on their observations, when FXRα’s activation is enhanced in the presence of UDCA bound to IBABP, more major human bile acids are released from cells called ileocytes, which are otherwise held back in liver disease and can cause cirrhosis.

Reference
  1. 1. Fang, C. et al. J. Lipid Research. doi: 10.1194/jlr.M021733 (2012).

Mary L. Chang (mchang@asbmb.org) is managing editor of the Journal of Lipid Research and coordinating journal manager of Molecular and Cellular Proteomics.


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