Cholestasis is an important manifestation of liver disease. Although previous work has suggested that bile formation consists of mechanistically distinct components related to and independent of bile acid secretion, the responsible cellular mechanisms and the possible relationships of these components are poorly understood. Recent findings by the PI and others suggest that these components of bile secretion are closely interrelated and directly mediated or regulated by ATP binding cassette (ABC) proteins. These findings indicate that rat hepatocytes express several novel ABC proteins in addition to those previously recognized. They further suggest that hepatocellular ABC proteins are, collectively, multifunctional. The proposed studies will test the hypothesis that known and novel ABC proteins expressed in hepatocytes mediate or regulate several interrelated functions critical to bile formation, including (a) ATP-dependent canalicular secretion of bile acids, (b) bile acid-regulatable secretion of the signaling molecule, ATP, which acts on biliary purinergic receptors to stimulate ductular secretion of fluid and electrolytes, and (c) chloride transport which modulates bile acid secretion through changes in liver cell volume. This hypothesis is based upon preliminary studies that demonstrate the feasibility of the proposed strategies for identifying and functionally characterizing known as well as novel hepatocellular ABC proteins that mediate these specific functions. The proposed studies will define the molecular mechanisms for (a) active bile acid secretion, (b) paracrine coupling of canalicular and ductular secretion via regulated canalicular release of the signaling molecule ATP, and (c) regulation of bile acid-secretory capacity via cell swelling induced by post-prandial uptake of solutes such as bile acids and amino acids. They also will provide important new information regarding a widely distributed family of transport proteins of broad biological as well as clinical interest.
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