Cellular and molecular biology of the liver

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Abstract
Recent advances in defining the cellcular 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 under goes transcriptional and posttranslational regulation and is downregulated in cholestasis. A novel organic anion-transporting 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 transports, and vesicular trafficking is regulated by phosphoinositide-3-kinase (Pl3K) and protein phosphatases 1 and 2A. Canalicular bile acid transport may be medicated 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 downregulate 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 Pl3K in bile acid-induced apoptosis have been proposed.

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