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.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW006153-03
Application #
6876140
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Primack, Aron
Project Start
2003-03-03
Project End
2006-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$34,880
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Amigo, Ludwig; Quinones, Veronica; Leiva, Andrea et al. (2011) Apolipoprotein A-I deficiency does not affect biliary lipid secretion and gallstone formation in mice. Liver Int 31:263-71
Rigotti, Attilio (2007) Absorption, transport, and tissue delivery of vitamin E. Mol Aspects Med 28:423-36
Yesilaltay, Ayce; Morales, Maria Gabriela; Amigo, Ludwig et al. (2006) Effects of hepatic expression of the high-density lipoprotein receptor SR-BI on lipoprotein metabolism and female fertility. Endocrinology 147:1577-88
Yesilaltay, Ayce; Kocher, Olivier; Pal, Rinku et al. (2006) PDZK1 is required for maintaining hepatic scavenger receptor, class B, type I (SR-BI) steady state levels but not its surface localization or function. J Biol Chem 281:28975-80
Yesilaltay, Ayce; Kocher, Olivier; Rigotti, Attilio et al. (2005) Regulation of SR-BI-mediated high-density lipoprotein metabolism by the tissue-specific adaptor protein PDZK1. Curr Opin Lipidol 16:147-52
Zanlungo, Silvana; Rigotti, Attilio; Nervi, Flavio (2004) Hepatic cholesterol transport from plasma into bile: implications for gallstone disease. Curr Opin Lipidol 15:279-86
Kocher, Olivier; Yesilaltay, Ayce; Cirovic, Christine et al. (2003) Targeted disruption of the PDZK1 gene in mice causes tissue-specific depletion of the high density lipoprotein receptor scavenger receptor class B type I and altered lipoprotein metabolism. J Biol Chem 278:52820-5