Lipid-Free Apolipoprotein A-I Reduces Progression of Atherosclerosis by Mobilizing Microdomain Cholesterol and Attenuating the Number of CD131 Expressing Cells: Monitoring Cholesterol Homeostasis Using the Cellular Ester to Total Cholesterol Ratio.
Atherosclerosis is a chronic inflammatory disorder whose development is inversely correlated with high-density lipoprotein concentration. Current therapies involve pharmaceuticals that significantly elevate plasma high-density lipoprotein cholesterol concentrations. Our studies were conducted to investigate the effects of low-dose lipid-free apolipoprotein A-I (apoA-I) on chronic inflammation. The aims of these studies were to determine how subcutaneously injected lipid-free apoA-I reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without sustained elevations in plasma high-density lipoprotein cholesterol concentrations.



Ldlr-/-and Ldlr-/-apoA-I-/-mice were fed a Western diet for a total of 12 weeks. After 6 weeks, a subset of mice from each group received subcutaneous injections of 200 μg of lipid-free human apoA-I 3 times a week, while the other subset received 200 μg of albumin, as a control. Mice treated with lipid-free apoA-I showed a decrease in cholesterol deposition and immune cell retention in the aortic root compared with albumin-treated mice, regardless of genotype. This reduction in atherosclerosis appeared to be directly related to a decrease in the number of CD131 expressing cells and the esterified cholesterol to total cholesterol content in several immune cell compartments. In addition, apoA-I treatment altered microdomain cholesterol composition that shifted CD131, the common β subunit of the interleukin 3 receptor, from lipid raft to nonraft fractions of the plasma membrane.



ApoA-I treatment reduced lipid and immune cell accumulation within the aortic root by systemically reducing microdomain cholesterol content in immune cells. These data suggest that lipid-free apoA-I mediates beneficial effects through attenuation of immune cell lipid raft cholesterol content, which affects numerous types of signal transduction pathways that rely on microdomain integrity for assembly and activation.
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
Sushma
S
Kaul
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
Hao
H
Xu
Section of Molecular Medicine, and Biochemistry, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
Manal
M
Zabalawi
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
Elisa
E
Maruko
Section of Molecular Medicine, and Biochemistry, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
Brian E
BE
Fulp
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
Theresa
T
Bluemn
Section of Molecular Medicine, and Biochemistry, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
Kristina L
KL
Brzoza-Lewis
Section of Molecular Medicine, and Biochemistry, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
Mark
M
Gerelus
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
Ranjuna
R
Weerasekera
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI.
Rachel
R
Kallinger
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI.|TOPS Obesity and Metabolic Research Center, Medical College of Wisconsin, Milwaukee, WI.
Roland
R
James
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI.|TOPS Obesity and Metabolic Research Center, Medical College of Wisconsin, Milwaukee, WI.
Yi Sherry
YS
Zhang
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI.
Michael J
MJ
Thomas
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI msthomas@mcw.edu.|Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI.
Mary G
MG
Sorci-Thomas
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016632:Apolipoprotein A-I / Q000235:genetics / Q000494:pharmacology*; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D053648:Cytokine Receptor Common beta Subunit; D066273:Diet, Western; D006706:Homeostasis; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008077:Lipoproteins, LDL; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D011973:Receptors, LDL / Q000235:genetics
D016632:Apolipoprotein A-I; D002788:Cholesterol Esters; D053648:Cytokine Receptor Common beta Subunit; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002784:Cholesterol
apolipoprotein; apolipoprotein A‐I; cholesterol; chronic inflammation; high‐density lipoprotein; inflammation; lipid rafts; microdomains; signaling pathways