Cellular and molecular biology of the liver

Recent advances in defining the cellular and molecular mechanisms regulating hepatocellular solute transport and injury are discussed in this chapter, Hepatic uptake of bile acid by means of Na+/taurocholate-cotransporting polypeptide undergoes transcriptional and posttranslational regulation and is downregulated in cholestasis, A novel organic anion-transport ing protein (oatp2) is expressed in the liver and transports cardiac glycosides. Conjugated bile acid uptake by hepatocytes and ductular cells may involve anion exchange. Microtubule-sensitive pathways are proposed to be involved in the delivery of ATP-dependent canalicular transporters, and vesicular trafficking is regulated by phosphoinositide-3-kinase (PI3K) and protein phosphatases 1 and 2A. Canalicular bile acid transport may be mediated via proteins other than ecto-ATPase, and is regulated by mitogen-activated protein kinases, A mutation in the canalicular multispecific organic anion transporter (cmoat/mrp2) may explain impaired non-bile acid organic anion transport in Dubin-Johnson syndrome, and this transporter may be downregulated in cholestasis. Ischemia-reperfusion results in altered activity of the Na+/HCO3- cotransporter and the Na+-H+ exchanger, and the latter may play an important role in growth factor-induced proliferation of hepatic stellate cells. Cholangiocyte Cl-/HCO3- exchanger is regulated by protein kinase A and protein phosphatases, and is downregulated in primary biliary cirrhosis. Endotoxin-induced cholestasis is not mediated via nitric oxide (NO) or cGMP, and the production of NO in endotoxemia may be a protective mechanism. Further support for a role of calpain proteases and mitochondrial membrane permeability transition is presented, and roles for protein kinase C and PI3K in bile acid-induced apoptosis have been proposed.