Cellular Regulation of Hepatic Bile Acid Transport in Health and Cholestasis

Abstract

Our understanding of bile acid transporters and their substrates and locations has increased steadily as has our understanding of the cellular mechanism regulating these transporters. It is becoming more evident that choleretic and cholestatic agents modify the function of these transporters through various signal transduction pathways. Nuclear receptors regulate transcription of various transporter genes. cAMP stimulates transhepatic transport of bile acids by translocating Ntcp and Bsep to the sinusoidal and the canalicular membrane, respectively. The PI3K signaling pathway is involved in biliary excretion of bile acids and taurolithocholate-induced activation of PKCε. Tauroursodeoxycholate stimulates biliary bile acid excretion via the P38 MAPK signaling pathway and reverses TLC cholestasis by stimulating PKC-mediated translocation of Mrp2 to the canalicular membrane. Calcium, acting via Ca2+/calmodulin dependent kinases/phosphatases, augments cAMP-mediated translocation of Ntcp. PKC stimulates bile acid secretion, most likely by phosphorylating Bsep. However, the role of specific PKC isoforms involved in bile formation and cholestasis is still unclear. Molecular mechanisms by which PI3K and MAPK signaling pathways stimulate transporter translocation along the cytoskeleton have not been elucidated. Our knowledge of the role of protein phosphatases and nuclear receptors in bile formation and cholestasis is rather limited. It is, however, anticipated that further understanding in these areas will be forthcoming in the near future.