Increased LDL Cholesterol and Atherosclerosis in LDL Receptor–Deficient Mice With Attenuated Expression of Scavenger Receptor B1

Author:

Huszar Dennis1,Varban Mariet Lee1,Rinninger Franz1,Feeley Roslyn1,Arai Takeshi1,Fairchild-Huntress Victoria1,Donovan Michael J.1,Tall Alan R.1

Affiliation:

1. From Millennium Pharmaceuticals, Inc (D.H., M.L.V., R.F., V.F.-H., M.J.D.), Cambridge, Mass; the Division of Molecular Medicine (F.R., T.A., A.R.T.), Department of Medicine, Columbia University, New York, NY; and Universitat Hamburg (F.R.), Krankenhaus Eppendorf, Medizinische Klinik, Hamburg, Germany.

Abstract

Abstract —Scavenger receptor BI (SR-BI) is a multiligand cell-surface receptor that plays a central role in high density lipoprotein homeostasis in rodents. To investigate a role for SR-BI in atherosclerosis, mice with attenuated SR-BI expression were crossed with low density lipoprotein (LDL) receptor–deficient mice. Compound-homozygous mutants showed increased plasma cholesterol, surprisingly due primarily to increased LDL cholesterol and apolipoprotein B levels. LDL turnover studies showed that this resulted from increased LDL cholesterol production rather than decreased LDL catabolism. Atherosclerotic lesion size was significantly increased in male compound-mutant mice relative to LDL receptor–deficient controls (93 427±16 079 versus 34 448±5 331 μm 2 , respectively; P =0.003). The proatherogenic effect of attenuated SR-BI expression may in part be due to increased LDL cholesterol levels. These findings suggest that upregulation of the receptor could have therapeutic potential for the treatment of atherosclerosis.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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