title: A coding variant in SR-BI (I179N) significantly increases atherosclerosis in mice.
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.
authors.affiliation: Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, 654 BRBII/III Labs, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors.forename: Antonino
authors.initials: A
authors.lastname: Picataggi
authors.forename: Geoffrey F
authors.initials: GF
authors.lastname: Lim
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Kent
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Ioannis M
authors.initials: IM
authors.lastname: Stylianou
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D008099:Liver / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000235:genetics*; D051122:Scavenger Receptors, Class B / Q000235:genetics*; D013163:Splenomegaly / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B