Effect of macrophage-derived apolipoprotein E on hyperlipidemia and atherosclerosis of LDLR-deficient mice.
LDL receptor-deficient (LDLR(-/-)) mice fed a Western diet exhibit severe hyperlipidemia and develop significant atherosclerosis. Apolipoprotein E (apoE) is a multifunctional protein synthesized by hepatocytes and macrophages. We sought to determine effect of macrophage apoE deficiency on severe hyperlipidemia and atherosclerosis. Female LDLR(-/-) mice were lethally irradiated and reconstituted with bone marrow from either apoE(-/-) or apoE(+/+) mice. Four weeks after transplantation, recipient mice were fed a Western diet for 8 weeks. Reconstitution of LDLR(-/-) mice with apoE(-/-) bone marrow resulted in a slight reduction in plasma apoE levels and a dramatic reduction in accumulation of apoE and apoB in the aortic wall. Plasma lipid levels were unaffected when mice had mild hyperlipidemia on a chow diet, whereas IDL/LDL cholesterol levels were significantly reduced when mice developed severe hyperlipidemia on the Western diet. The hepatic VLDL production rate of mice on the Western diet was decreased by 46% as determined by injection of Triton WR1339 to block VLDL clearance. Atherosclerotic lesions in the proximal aorta were significantly reduced, partially due to reduction in plasma total cholesterol levels (r=0.56; P<0.0001). Thus, macrophage apoE-deficiency alleviates severe hyperlipidemia by slowing hepatic VLDL production and consequently reduces atherosclerosis in LDLR(-/-) mice.
Shi
Weibin
W
Department of Radiology, University of Virginia, Charlottesville 22908, USA. ws4v@virginia.edu
Wang
Xuping
X
Wong
Jack
J
Hedrick
Catherine C
CC
Wong
Howard
H
Castellani
Lawrence W
LW
Lusis
Aldons J
AJ
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001055:Apolipoproteins B / Q000378:metabolism; D001057:Apolipoproteins E / Q000097:blood / Q000172:deficiency* / Q000494:pharmacology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood; D015243:Cholesterol, VLDL / Q000096:biosynthesis; D004036:Diet, Atherogenic; D005260:Female; D006949:Hyperlipidemias / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008071:Lipoprotein Lipase / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D001057:Apolipoproteins E; D015243:Cholesterol, VLDL; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase