Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1.
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 microm(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.
Huszar
D
D
Millennium Pharmaceuticals, Inc, Cambridge, MA 02139, USA. huszar@mpi.com
Varban
M L
ML
Rinninger
F
F
Feeley
R
R
Arai
T
T
Fairchild-Huntress
V
V
Donovan
M J
MJ
Tall
A R
AR
D000818:Animals; D001011:Aorta / Q000473:pathology; D001055:Apolipoproteins B / Q000097:blood; D001057:Apolipoproteins E / Q000097:blood; D001161:Arteriosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D004032:Diet; D015870:Gene Expression; D006720:Homozygote; D008055:Lipids / Q000097:blood; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
D001055:Apolipoproteins B; D001057:Apolipoproteins E; D018955:CD36 Antigens; D008078:Cholesterol, LDL; D008055:Lipids; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol