Relationship between expression levels and atherogenesis in scavenger receptor class B, type I transgenics.
Both in vitro and in vivo studies of scavenger receptor class B type I (SR-BI) have implicated it as a likely participant in the metabolism of HDL cholesterol. To investigate the effect of SR-BI on atherogenesis, we examined two lines of SR-BI transgenic mice with high (10-fold increases) and low (2-fold increases) SR-BI expression in an inbred mouse background hemizygous for a human apolipoprotein (apo) B transgene. Unlike non-HDL cholesterol levels that minimally differed in the various groups of animals, HDL cholesterol levels were inversely related to SR-BI expression. Mice with the low expression SR-BI transgene had a 50% reduction in HDL cholesterol, whereas the high expression SR-BI transgene was associated with 2-fold decreases in HDL cholesterol as well as dramatic alterations in HDL composition and size including the near absence of alpha-migrating particles as determined by two-dimensional electrophoresis. The low expression SR-BI/apo B transgenics had more than a 2-fold decrease in the development of diet-induced fatty streak lesions compared with the apo B transgenics (4448 +/- 1908 micrometer(2)/aorta to 10133 +/- 4035 micrometer (2)/aorta; p < 0.001), whereas the high expression SR-BI/apo B transgenics had an atherogenic response similar to that of the apo B transgenics (14692 +/- 7238 micrometer(2)/aorta) but 3-fold greater than the low SR-BI/apo B mice (p < 0.001). The prominent anti-atherogenic effect of moderate SR-BI expression provides in vivo support for the hypothesis that HDL functions to inhibit atherogenesis through its interactions with SR-BI in facilitating reverse cholesterol transport. The failure of the high SR-BI/apo B transgenics to have similar or even greater reductions in atherogenesis suggests that the changes resulting from extremely high SR-BI expression including dramatic changes in lipoproteins may have both pro- and anti-atherogenic consequences, illustrating the complexity of the relationship between SR-BI and atherogenesis.
Ueda
Y
Y
Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Gong
E
E
Royer
L
L
Cooper
P N
PN
Francone
O L
OL
Rubin
E M
EM
D000818:Animals; D001011:Aorta / Q000473:pathology; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000235:genetics*; D018955:CD36 Antigens / Q000097:blood / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D004036:Diet, Atherogenic; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006651:Histocytochemistry; D006801:Humans; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D011971:Receptors, Immunologic; D011973:Receptors, LDL / Q000235:genetics; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D012260:Ribonucleases / Q000378:metabolism; D051122:Scavenger Receptors, Class B
D001055:Apolipoproteins B; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D008055:Lipids; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D012260:Ribonucleases