Hepatobiliary transport: molecular mechanisms of development and cholestasis

The secretion of bile requires the vectorial transport of organic and inorganic solutes from sinusoidal blood to the canalicular lumen. Hydrostatic forces cannot account for biliary secretion, because secretory pressures within bile ducts exceed that of blood within the sinusoidal space. Instead, the process of bile formation requires active transport across the basolateral membrane, transcellular movement through a variety of mechanisms, and then active transport into the canalicular space between hepatocytes. Separate hepatic and ductular transport mechanisms allow for rapid regulation of bile volume and composition required for changing physiologic needs. The array of transport proteins localized to both poles of the hepatocyte have been characterized physiologically and during development. Many have now been cloned and studied further in transgenic models. The recent identification and characterization of several genes that are mutated in inherited forms of cholestatic liver disease have provided new insight into the normal physiology of bile secretion, the pathophysiology of intrahepatic cholestasis, and an unexpected major role for a novel group of P-type ATPases in human biology and disease.