Pharmacy research at URI: bile acids and bile salt export pump: physiology and pathology.

mediciNe & HealtH/RHode iSlaNd the long-term objeCtIve of our reSearCh program is to understand how bile acid homeostasis is regulated in physiological as well as pathological conditions, with a focus on the transcriptional regulation of the bile salt export pump (BSEP). As one of the major constituents of bile, bile acids were once considered bodily waste with no useful functions. Now it is well established that bile acids have important physiological functions in animals and human. First, the well-known function of bile acids is to solubilize cholesterol and lipids in an aqueous environment, such as in the bile and the intestines. On the other hand, as biological detergents, too much bile acids are toxic for cells. Second, bile acids are recognized as signaling molecules serving as the endogenous ligands for nuclear receptor farnesoid x receptor (FXR) and G-protein-coupled receptor TGR5 to regulate cholesterol, bile acids and glucose homeostasis. Finally, recent studies have extended the functions of bile acids into various non-metabolic areas including inflammation, liver regeneration, hepatocarcinogenesis, inhibition of intestine bacterial growth and colon cancer. Bile acid homeostasis is achieved through coordinately regulated bile acid synthesis and elimination pathways. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme for bile acid synthesis while BSEP is the rate limitingstep in the enterohepatic circulation of bile acids. (Figure 1) Modulation of BSEP expression or function by inherited or acquired factors has profound impacts on bile acid homeostasis and subsequently contributes to the risk for various bile acids-associated diseases, including intrahepatic cholestasis, gallstone disease and hepatocellular carcinoma (HCC). Studying the transcriptional regulation of BSEP will uncover the mechanistic insights in the role BSEP plays in physiological as well as pathological conditions.