Molecular Physiology of Hepatic Transport

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DESCRIPTION (provided by applicant): Bile salt secretion is the major driving force for bile formation. Bile salts are amphipathic molecules that solubilize lipids and hydrophobic nutrients prior to gut absorption, enhance hepatobiliary secretion, prevent cholesterol gallstone formation and transcriptionally regulate many hepatic and intestinal genes involved in lipid metabolism. The rate-limiting step for hepatocellular bile salt transport is ATP-dependent canalicular secretion, and Abcb11 (BSEP) is the gene that encodes for this transporter. In humans, the inter-individual variability of Abcb11 is large. However, the in vivo effects of Abcb11 in both normal physiology and pathophysiologic states remain poorly understood. The Principal Investigator has recently developed transgenic transthyretin promoter-Abcbl 1 (TTR-Abcb11) mice that functionally over-express Abcb11 in the liver canalicular membrane. This mouse can allow 1 to perform novel in vivo investigations into the physiologic role of Abcbl 1. Thus, the Specific Aims of the proposal are: Specific Aim 1: To determine the mechanism(s) by which Abcb11 regulates gene expression in the liver and enterohepatic circulation, with the resultant effects on hepatobiliary and systemic lipid metabolism. Specific Aim 2: To define the mechanism(s) with which Abcb11 induces: fatty liver diseases and cholelithiasis, by feeding TTR-Abcb11 mice well-characterized murine diets that are nutritional models of these diseases. Specific Aim 3: To determine mechanisms by which hepatic Abcb11 regulates systemic lipid metabolism, hyperlipidemia and atherosclerosis by employing "classic" murine models of hypercholesterolemia. This proposal utilizes state-of-the-art mouse genetics, molecular biology and lipid biochemical techniques to examine the molecular mechanisms responsible for diseases including fatty liver, cholelithiasis and systemic lipid disorders. These studies will further our understanding of Abcbl 1 function on hepatic bile salt transport as well as hepatobiliary and systemic lipid metabolism. This data is critical for the development of rational therapies for common systemic disorders of lipid metabolism and diseases of the gallbladder and liver.