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.

Rare Genetic Variants and High-Density Lipoprotein

“…17,18,22 Studies in atherosclerosis-susceptible mice showed that inactivating SR-B1 globally or in a liver-specific manner increased atherosclerosis, whereas overexpressing SR-B1 in liver protected against atherosclerosis. 19,[23][24][25][26][27][28][29][30][31][32] These and other studies in mice [33][34][35] suggest a mechanism whereby SR-B1, by mediating hepatic selective HDL-C clearance from plasma, drives atheroprotective reverse cholesterol transport (RCT). Disrupting SR-B1 activity thus blocks hepatic HDL-selective uptake and backs up hepatic RCT, triggering an increase in HDL-C and impairs HDL-dependent cholesterol removal from atherosclerotic plaques.…”

Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1

“…Regarding the role of SR-B1 in CVD, it has been shown to protect from diet-induced atherosclerosis in apoE-/-mouse models [9,10] while SR-B1 deficient mice with high HDL-C, was associated with increased atherosclerosis and increased expression of inflammatory markers [7]. In line, it has also been shown that a coding variant for SR-B1 (I179N) caused increased atherosclerosis in LDL-receptor knockout mice on a Western-type diet [11]. In humans, variation at the SCARB1 locus (the gene encoding for SR-B1) has been associated to CVD, albeit in a gender specific way [12,13,14].…”

Single amino acid mutation of SR-BI decreases infectivity of hepatitis C virus derived from cell culture in a cell culture model

“…Then, two novel missense mutations, S112F and T175A, in human SR-BI were identified in patients with atherosclerosis, which led to elevated HDL cholesterol levels[ 27 ]. A coding variant in SR-BI (I179N) significantly increased atherosclerosis, although the mutation did not dramatically affect the plasma lipid levels[ 34 ]. The hydrophobicity of N-terminal half of the extracellular domain of SR-BI was proven to be critical for the SR-BI-mediated cholesterol transport function, and this domain might function by interacting with other integral membrane proteins[ 35 - 37 ].…”