We utilize live cell fluorescent, biochemical, genetic and molecular techniques to study mechanisms responsible for trafficking of proteins selectively to the apical domain of hepatocytes and other polarized cells. These proteins include specific ATP-dependent transporters for bile acids, phospholipids, nonbile acid organic anions, and sterols. The goal is to identify components and regulation of these processes, their role in creating and maintaining hepatocyte polarity, and molecular defects responsible for inheritable and acquired bile secretory failure (cholestasis). To date, numerous specific proteins and lipids have been identified which are critical for trafficking, membrane fusion and recycling of the apical transporters. Genetic and pharmacologic manipulation of these factors results in defective biliary secretion (cholestasis). Our studies indicate a dependent relationship between cellular polarity and the apical trafficking systems. It is likely that acquired cholestasis, due to drugs, viruses, hyperalimentation and other factors, results from an intracellular traffic jam affecting the cellular-molecular events we have described.
