CELLULAR AND MOLECULAR-BIOLOGY OF THE LIVER

Recent advances in defining the cellular and molecular mechanisms regu lating hepatocellular solute transport and injury are discussed in thi s chapter, Hepatic uptake of bile acid by means of Na+/taurocholate-co transporting polypeptide undergoes transcriptional and posttranslation al regulation and is downregulated in cholestasis, A novel organic ani on-transport ing protein (oatp2) is expressed in the liver and transpo rts cardiac glycosides. Conjugated bile acid uptake by hepatocytes and ductular cells may involve anion exchange. Microtubule-sensitive path ways are proposed to be involved in the delivery of ATP-dependent cana licular transporters, and vesicular trafficking is regulated by phosph oinositide-3-kinase (PI3K) and protein phosphatases 1 and 2A. Canalicu lar bile acid transport may be mediated via proteins other than ecto-A TPase, and is regulated by mitogen-activated protein kinases, A mutati on in the canalicular multispecific organic anion transporter (cmoat/m rp2) may explain impaired non-bile acid organic anion transport in Dub in-Johnson syndrome, and this transporter may be downregulated in chol estasis. Ischemia-reperfusion results in altered activity of the Na+/H CO3- cotransporter and the Na+-H+ exchanger, and the latter may play a n important role in growth factor-induced proliferation of hepatic ste llate cells. Cholangiocyte Cl-/HCO3- exchanger is regulated by protein kinase A and protein phosphatases, and is downregulated in primary bi liary cirrhosis. Endotoxin-induced cholestasis is not mediated via nit ric oxide (NO) or cGMP, and the production of NO in endotoxemia may be a protective mechanism. Further support for a role of calpain proteas es and mitochondrial membrane permeability transition is presented, an d roles for protein kinase C and PI3K in bile acid-induced apoptosis h ave been proposed.