Apolipoprotein E-deficient lipoproteins induce foam cell formation by downregulation of lysosomal hydrolases in macrophages.
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.
Wu
DongFang
D
Department of Cardiovascular Biology, Meharry Medical College, Nashville, TN 37208, USA.
Sharan
Chakradhari
C
Yang
Hong
H
Goodwin
J Shawn
JS
Zhou
Lichun
L
Grabowski
Gregory A
GA
Du
Hong
H
Guo
ZhongMao
Z
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
D001057:Apolipoproteins E; D017527:Receptor, IGF Type 2; D006867:Hydrolases