Decreased Atherosclerosis in Heterozygous Low Density Lipoprotein Receptor-deficient Mice Expressing the Scavenger Receptor BI Transgene*
- From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032
Abstract
Scavenger receptor type B class I (SR-BI), initially identified as a receptor that recognizes low density lipoprotein (LDL), was recently shown to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl esters in liver and steroidogenic tissues. To evaluate effects on atherosclerosis, transgenic mice with liver-specific overexpression of SR-BI (SR-BI Tg mice) have been crossed onto LDL receptor-deficient backgrounds. To induce atherosclerosis in a setting of moderate hypercholesterolemia, heterozygous LDL receptor-deficient mice (LDLR1) were fed a high fat/cholesterol/bile salt diet, and homozygous LDL receptor knock-outs (LDLR0) were fed a high fat/cholesterol diet. LDLR1/SR-BI Tg mice showed decreases in VLDL, LDL, and HDL cholesterol and a significant 80% decrease in mean lesion area in the aortic root compared with LDLR1 mice (female LDLR1 74, 120 μm2 versus LDLR1/SR-BI Tg 12, 667 μm2; male 25, 747 μm2 versus 5, 448 μm2, respectively). LDLR0/SR-BI Tg mice showed decreased LDL and HDL cholesterol but increased VLDL cholesterol and no significant difference in extent of atherosclerosis compared with LDLR0 mice. Combined data analysis showed a strong correlation between atherosclerotic lesion area and the VLDL+LDL cholesterol level but no correlation with HDL level. These studies demonstrate a strong anti-atherogenic potential of hepatic SR-BI overexpression. In mice with marked overexpression of SR-BI, the protective effect appears to be primarily related to the lowering of VLDL and LDL cholesterol levels.
Footnotes
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↵* This work was supported by National Institutes of Health Grants HL54591, HL58033, and HL21006 and by Lilly Research Labs and Millenium.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: Div. of Molecular Medicine, Dept. of Medicine, Columbia University, New York, NY 10032. Tel.: 212-305-4899; Fax: 212-305-5052.
- Abbreviations:
- SR-BI
-
scavenger receptor type B class I
- TC
-
total cholesterol
- CE
-
cholesteryl ester
- apo
-
apolipoprotein
- LDL
-
low density lipoprotein(s)
- VLDL
-
very LDL
- HDL
-
high density lipoprotein
- Tg
-
transgenic (mice)
- LDLRKO
-
LDL receptor knockout mice
- FPLC
-
fast protein chromatography
- PAGE
-
polyacrylamide gel electrophoresis.
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- Received November 19, 1998.
- Revision received December 3, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
