Apolipoprotein A-I and Its Role in Lymphocyte Cholesterol Homeostasis and Autoimmunity

Abstract

Objective-The purpose of this study was to determine the effects of an atherogenic diet on immune function in LDLr Ϫ/Ϫ , ApoA-I Ϫ/Ϫ mice. Methods and Results-When LDLrϪ/Ϫ , ApoA-I Ϫ/Ϫ (DKO), and LDLr Ϫ/Ϫ (SKO) mice were fed an atherogenic diet, DKO had larger peripheral lymph nodes (LNs) and spleens compared to SKO mice. LNs were enriched in cholesterol and contain expanded populations of T, B, dendritic cells, and macrophages. Expansion of all classes of LN cells was accompanied by a Ϸ1.5-fold increase in T cell proliferation and activation. Plasma antibodies to dsDNA, ␤2-glycoprotein I, and oxidized LDL were increased in DKO, similar to levels in diet-fed Fas lpr/lpr mice, suggesting the development of an autoimmune phenotype. Both LN enlargement and cellular cholesterol expansion were "prevented" when diet-fed DKO mice were treated with helper dependent adenovirus expressing apoA-I. Independent of the amount of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation. Conclusions-ApoA-I prevented cholesterol-associated lymphocyte activation and proliferation in peripheral LN of diet-fed DKO mice. A Ϸ1.5-fold increase in T cell activation and proliferation was associated with a Ϸ3-fold increase in concentrations of circulating autoantibodies and Ϸ2-fold increase in the severity of atherosclerosis suggesting a common link between plasma apoA-I, inflammation, and atherosclerosis.

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

“…It has been shown to be a key player in macrophage reverse cholesterol transport regulation through its capacity to package large amounts of cholesterol following its interaction with ABCA1 on cell membranes 29, 56. Interestingly, subcutaneously injected lipid‐free apoA‐I has been reported to reduce accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without increasing HDL‐cholesterol concentrations 33, 57. Whereas apoA‐I has been extensively studied in the past decade, the mechanisms by which it mediates its atheroprotective effect are still unclear.…”

Macrophage apoAI protects against dyslipidemia-induced dermatitis and atherosclerosis without affecting HDL

“…mice rescued them from the fatal dyslipidemia-induced dermatitis by reducing skin cholesterol accumulation and infl ammation ( 27,28 ).…”

Nascent high density lipoproteins formed by ABCA1 resemble lipid rafts and are structurally organized by three apoA-I monomers

“…Lipids were extracted from the dried nHDL Peaks #1-4 according to Bligh and Dyer ( 36 ) after adding 4 µg of [3,4-14 C 2 ] cholesterol as the internal standard for cholesterol analyses ( 9 ). Lipid extracts were evaporated under a stream of argon, dissolved in 1 ml of chloroform-methanol (1:1), and stored at Ϫ 80°C until analyzed.…”

“…An aliquot from each of the Peak #1-4 lipid extracts was evaporated under argon, dissolved in toluene, and analyzed on a Finnigan Trace 2000 mass spectrometer or a Finnigan TSQ Quantum XLS tandem mass spectrometer interfaced to a Trace gas chromatograph ( 9 ). A second 50 µl aliquot was saponifi ed at room temperature for 2 h with methanolic-KOH (similar to a reported procedure using ethanol), cooled, and then extracted with hexane.…”

“…I-apoA-I or 3 H-cholesterol (Perkin decreases in production of plasma HDL, ABCA1 dysfunction can also signifi cantly alter cell signaling by modulating membrane cholesterol levels, leading to hyperactive immune cells (8)(9)(10). Most recently, studies have shown that ABCA1 functions to maintain cellular cholesterol content within membrane microdomains, such as lipid rafts ( 8,11 ).…”