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Originally published In Press as doi:10.1194/jlr.M700217-JLR200 on August 25, 2007

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Journal of Lipid Research, Vol. 48, 2571-2578, December 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Apolipoprotein E-deficient lipoproteins induce foam cell formation by downregulation of lysosomal hydrolases in macrophages

DongFang Wu*, Chakradhari Sharan*, Hong Yang*, J. Shawn Goodwin{dagger}, Lichun Zhou*, Gregory A. Grabowski§, Hong Du§ and ZhongMao Guo1,*

* Department of Cardiovascular Biology, Meharry Medical College, Nashville, TN 37208
{dagger} Department of Cancer Biology, Meharry Medical College, Nashville, TN 37208
§ Division and Program in Human Genetics, Children's Hospital Research Foundation, Cincinnati, OH 45229

Published, JLR Papers in Press, August 25, 2007.

1 To whom correspondence should be addressed. e-mail: zguo{at}mmc.edu

Apolipoprotein E (apoE) deficiency has been suggested to induce foam cell formation. Using lipoproteins obtained from wild-type mice and apoE-deficient mice expressing apoB-48 but not apoB-100, we studied apoE-deficient lipoprotein-induced changes in lipoprotein catabolism and protein expression in mouse peritoneal macrophages (MPMs). Our data demonstrate that incubation of MPMs with apoE-deficient lipoproteins induced intracellular lipoprotein, cholesteryl ester, and triglyceride accumulation, which was associated with a time-related decline in apoE-deficient lipoprotein degradation in MPMs. Confocal microscopy analysis indicated that the accumulated lipids were localized in lysosomes. ApoE-deficient lipoproteins reduced the protein levels of lysosomal acid lipase, cathepsin B, and cation-dependent mannose 6 phosphate receptor (MPR46). Exogenous apoE reduced apoE-deficient lipoprotein-induced lipid accumulation and attenuated the suppressive effect of apoE-deficient lipoproteins on lysosomal hydrolase and MPR46 expression. Although oxidized lipoproteins also increased lipid contents in MPMs, exogenous apoE could not attenuate oxidized lipoprotein-induced lipid accumulation. Our in vivo studies also showed that feeding apoE-deficient mice a high-fat diet resulted in cholesteryl ester and triglyceride accumulation and reduced lysosomal hydrolase expression in MPMs. These data suggest that apoE-deficient lipoproteins increase cellular lipid contents through pathways different from those activated by oxidized lipoproteins and that reducing lysosomal hydrolases in macrophages might be a mechanism by which apoE-deficient lipoproteins result in intralysosomal lipoprotein accumulation, thereby inducing foam cell formation.

Abbreviations: apoB, apolipoprotein B; apoB-48R, apolipoprotein B-48 receptor; E–/B48, apolipoprotein E-deficient, apolipoprotein B-48-containing lipoprotein; EC, esterified cholesterol; FC, free cholesterol; LDLR, low density lipoprotein receptor; MPM, mouse peritoneal macrophage; MPR46, cation-dependent mannose 6 phosphate receptor; SR, scavenger receptor; SR-A, scavenger receptor class A; SR-BI, scavenger receptor class B type I; TBARS, thiobarbituric acid-reacting substances

Supplementary key words oxidized lipoproteins • cholesterol ester • mannose 6 phosphate receptor


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