Hepatic overexpression of bovine scavenger receptor type I in transgenic mice prevents diet-induced hyperbetalipoproteinemia.
Hepatic scavenger receptors (SR) may play a protective role by clearing modified lipoproteins before they target the artery wall. To gain insight into this hypothesized function, transgenic mice expressing hepatic bovine SR (TgSR) were created and studied when fed chow, and during diet-induced hyperlipidemia. SR overexpression resulted in extensive hepatic parenchymal cell uptake of fluorescently labeled acetylated human low density lipoprotein (DiI ac-hLDL) and a twofold increase in 125I-acetylated-LDL clearance. Food intake and cholesterol absorption was indistinguishable between control and TgSR mice. In chow-fed mice, lipoprotein cholesterol was similar in control and TgSR mice. However, on a 3-wk high fat/cholesterol (HFHC) diet, the rise in apoB containing lipoproteins was suppressed in TgSR+/- and TgSR+/+ mice. The rise in HDL was similar in control and TgSR+/- mice, but significantly elevated in the TgSR+/+ mice. Overall, on chow, the ratio of apo-B containing lipoprotein cholesterol to HDL cholesterol was similar for all groups (control = 0.33; TgSR+/- = 0.32; TgSR+/+ = 0.38). However, after 3 wk on the HFHC diet, this ratio was markedly higher in control (2.34 +/- 0.21) than in either TgSR+/- (1.00 +/- 0.24) or TgSR+/+ (1.00 +/- 0.19) mice. In TgSR+/- mice, hepatic cholesteryl esters were reduced by 59%, 7 alpha-hydroxylase mRNA levels were elevated twofold, and a significant increase in fecal bile acid flux was observed after the 3-wk HFHC diet. These results suggest SR may play a protective role in liver by preventing diet-induced increases in apoB containing lipoproteins.
Wölle
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S
Department of Atherosclerosis Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, Michigan 48105, USA.
Via
D P
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Chan
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Cornicelli
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Bisgaier
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D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000032:analysis; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism; D004032:Diet; D005243:Feces / Q000737:chemistry; D006938:Hyperlipoproteinemia Type II / Q000209:etiology / Q000517:prevention & control*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics; D011973:Receptors, LDL / Q000502:physiology; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013261:Sterols / Q000097:blood
D001647:Bile Acids and Salts; D008055:Lipids; D008565:Membrane Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013261:Sterols; D002784:Cholesterol