title: Apolipoprotein E-deficient lipoproteins induce foam cell formation by downregulation of lysosomal hydrolases in macrophages.
abstract: 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.
authors.affiliation: Department of Cardiovascular Biology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: DongFang
authors.initials: D
authors.lastname: Wu
authors.forename: Chakradhari
authors.initials: C
authors.lastname: Sharan
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: J Shawn
authors.initials: JS
authors.lastname: Goodwin
authors.forename: Lichun
authors.initials: L
authors.lastname: Zhou
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.forename: ZhongMao
authors.initials: Z
authors.lastname: Guo
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005487:Foam Cells / Q000378:metabolism*; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010084:Oxidation-Reduction; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D017527:Receptor, IGF Type 2; D006867:Hydrolases