Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues.
Scavenger receptor SR-BI has been implicated in HDL-dependent atheroprotective mechanisms. We report the generation of an SR-BI conditional knockout mouse model in which SR-BI gene targeting by loxP site insertion produced a hypomorphic allele (hypomSR-BI). Attenuated SR-BI expression in hypomSR-BI mice resulted in 2-fold elevation in plasma total cholesterol (TC) levels. Cre-mediated SR-BI gene inactivation of the hypomorphic SR-BI allele in hepatocytes (hypomSR-BI-KO(liver)) was associated with high plasma TC concentrations, increased plasma free cholesterol/TC (FC/TC) ratio, and a lipoprotein-cholesterol profile typical of SR-BI-/- mice. Plasma TC levels were increased 2-fold in hypomSR-BI and control mice fed an atherogenic diet, whereas hypomSR-BI-KO(liver) and SR-BI-/- mice developed severe hypercholesterolemia due to accumulation of FC-rich, VLDL-sized particles. Atherosclerosis in hypomSR-BI mice was enhanced (2.5-fold) compared with that in controls, but to a much lower degree than in hypomSR-BI-KO(liver) (32-fold) and SR-BI-/- (48-fold) mice. The latter models did not differ in either plasma lipid levels or in the capacity of VLDL-sized lipoproteins to induce macrophage cholesterol loading. However, reduced atherosclerosis in hypomSR-BI-KO(liver) mice was associated with decreased lesional macrophage content as compared with that in SR-BI-/- mice. These data imply that, in addition to its major atheroprotective role in liver, SR-BI may exert an antiatherogenic role in extrahepatic tissues.
Huby
Thierry
T
INSERM U551, Université Pierre et Marie Curie-Paris 6, Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, Paris, France. huby@chups.jussieu.fr
Doucet
Chantal
C
Dachet
Christiane
C
Ouzilleau
Betty
B
Ueda
Yukihiko
Y
Afzal
Veena
V
Rubin
Edward
E
Chapman
M John
MJ
Lesnik
Philippe
P
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000483:Alleles; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001053:Apolipoproteins / Q000097:blood; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D004036:Diet, Atherogenic; D005260:Female; D015870:Gene Expression / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D008074:Lipoproteins / Q000097:blood / Q000737:chemistry / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051122:Scavenger Receptors, Class B / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors; D014280:Triglycerides / Q000097:blood; D000097382:CD68 Molecule
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001053:Apolipoproteins; D002784:Cholesterol; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D015850:Interleukin-6; D008074:Lipoproteins; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; C487540:ABCG1 protein, mouse; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C454739:Scarb1 protein, mouse