Abstract
Human coding variants in scavenger receptor class B member 1 (SR-BI; gene name SCARB1) have recently been identified as being associated with plasma levels of HDL cholesterol. However, a link between coding variants and atherosclerosis has not yet been established. In this study we set out to examine the impact of a SR-BI coding variant in vivo. A mouse model with a coding variant in SR-BI (I179N), identified through a mutagenesis screen, was crossed with Ldlr −/− mice, and these mice were maintained on a Western-type diet to promote atherosclerosis. Mice showed 56 and 125 % increased atherosclerosis in female and male Ldlr −/− Scarb1 I179N mice, respectively, when compared to gender-matched Ldlr −/− control mice. As expected, HDL cholesteryl ester uptake was impaired in Ldlr −/− Scarb1 I179N mice compared to Ldlr –/– control mice, with a net effect of increased small and very small LDL cholesterol in Ldlr −/− Scarb1 I179N mice being the most probable cause of the observed increased atherosclerosis. Our data show that non-null coding variants in SR-BI can have a large significant impact on atherosclerosis, even if plasma lipid levels are not dramatically affected, and that human mutations in other candidate lipid genes could significantly impact atherosclerosis.
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Acknowledgments
The authors thank Debra Cromley, Aisha Wilson, Edwige Edouard, and Mao-Sen Sun for technical assistance. Support was provided to IMS by the AHA Scientist Development Award (09SDG2280011).
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Picataggi, A., Lim, G.F., Kent, A.P. et al. A coding variant in SR-BI (I179N) significantly increases atherosclerosis in mice. Mamm Genome 24, 257–265 (2013). https://doi.org/10.1007/s00335-013-9459-x
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DOI: https://doi.org/10.1007/s00335-013-9459-x