Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels.
The risk of atherosclerosis, a leading cause of cardiovascular disease and death, is inversely related to plasma levels of high-density lipoprotein (HDL) cholesterol, although the mechanism of this protective effect is unclear. The class B scavenger receptor, SR-BI, is the first HDL receptor to be well defined at a molecular level and is a mediator of selective cholesterol uptake in vitro. It is expressed most abundantly in steroidogenic tissues, where it is coordinately regulated with steroidogenesis by adrenocorticotropic hormone (ACTH), human chorionic gonadotropin (hCG) and oestrogen, and in the liver, where its expression in rats is suppressed by oestrogen. Here we show that adenovirus-mediated, hepatic overexpression of SR-BI in mice on both sinusoidal and canalicular surfaces of hepatocytes results in the virtual disappearance of plasma HDL and a substantial increase in biliary cholesterol. SR-BI may directly mediate these effects by increasing hepatic HDL cholesterol uptake or by increasing cholesterol secretion into bile, or both. These results indicate that SR-BI may be important in hepatic HDL metabolism, in determining plasma HDL concentrations, and in controlling cholesterol concentrations in bile, and thus may influence the development and progression of atherosclerosis and gallstone disease.
Kozarsky
K F
KF
Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia 19104, USA. kozarsky@mail.med.upenn.edu
Donahee
M H
MH
Rigotti
A
A
Iqbal
S N
SN
Edelman
E R
ER
Krieger
M
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins; D002784:Cholesterol / Q000097:blood* / Q000493:pharmacokinetics; D005456:Fluorescent Dyes; D008075:Lipoproteins, HDL / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein / Q000097:blood* / Q000235:genetics; D051116:Receptors, Scavenger; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B
D018955:CD36 Antigens; D002352:Carrier Proteins; D005456:Fluorescent Dyes; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011994:Recombinant Proteins; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C031616:high density lipoprotein receptors; C075197:high density lipoprotein binding protein; D002784:Cholesterol