Hepatic Cholesterol Transport Mediated by SR-BI

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DESCRIPTION (provided by applicant) The liver is a key organ controlling body cholesterol homeostasis through the last step of reverse cholesterol transport pathway: the movement of cholesterol from plasma HDL into bile. The function of this pathway is under control of the hepatic expression and activity of the scavenger receptor class B type I (SR-BI). SR-BI is a multilipoprotein receptor that mediates selective uptake of HDL cholesterol. In vivo studies with mice, including overexpression of SR-BI in the liver and analysis of SR-BI homozygous null mutants, have shown that hepatic SR-BI expression plays a key role in determining plasma levels of HDL cholesterol, its uptake by liver cells and its efficient secretion into bile. Under physiological conditions, SR-BI might facilitate biliary cholesterol secretion by increasing intrahepatic cholesterol availability as a consequence of facilitated hepatic uptake of plasma lipoprotein cholesterol at the sinusoidal surface of hepatocytes. Because SR-BI can mediate cholesterol efflux and has been found in the canalicular membrane of SR-BI over-expressing liver cells, it might also be directly participating in biliary cholesterol secretion from the canalicular membrane. However, the precise structural features of SR-BI that determine its hepatic plasma membrane distribution and its function in hepatic cholesterol trafficking remain mostly unknown. The overall goals of this proposal are: 1) to elucidate the biochemical and structural bases for the polarized distribution of SR-BI in liver plasma membranes in vivo, and 2) to establish the structural determinants of SR-BI that underlie its functional activity in regulating the transport of cholesterol from plasma through the liver into bile. Various SR-BI mutant forms will be generated, utilized for recombinant adenoviral preparation, and tested for their effects on polarized plasma membrane localization and plasma HDL cholesterol levels and biliary cholesterol secretion in livers of mice infected with these recombinant adenoviruses. The proposed work will help to determine the key molecular and cellular mechanisms involved in SR-BI-mediated HDL cholesterol trafficking in the liver, and may provide new insights into the pathogenesis and treatment of atherosclerosis and gallstone disease, two frequent conditions associated with abnormal hepatic HDL metabolism. This research will be done by Attilio Rigotti primarily in Chile as an extension of NIH Grants # HL64737 and HL52212.