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

DongFang Wu, Chakradhari Sharan, Hong Yang, Shawn J. Goodwin, Lichun Zhou, Gregory A. Grabowski, and ZhongMao Guo

Cardiovascular Biology, Meharry Medical College, Nashiville, TN 37208

Corresponding Author: zguo{at}mmc.edu

Apolipoprotein (Apo) E deficiency has been suggested to induce foam cell formation. Using lipoproteins obtained from wild-type mice and ApoE-deficient mice expressing ApoB48 but not B100, this report studied ApoE-deficient lipoprotein-induced changes in lipoprotein catabolism and protein expression in mouse peritoneal macrophages (MPMs). Our data demonstrated that incubation of MPMs with ApoE-deficient lipoproteins induced intracellular lipoprotein, cholesterol 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 cholesterol ester and triglyceride accumulation, and reduced lysosomal hydrolase expression in MPMs. These data suggest that ApoE-deficient lipoproteins elevate cellular lipid contents through pathway(s) 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.

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