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Macrophage reverse cholesterol transport in mice expressing ApoA-I Milano.

ABSTRACT: To compare the abilities of human wild-type apoA-I (WT apoA-I) and human apoA-I(Milano) (apoA-I(M)) to promote macrophage reverse cholesterol transport (RCT) in apoA-I-null mice infected with adeno-associated virus (AAV) expressing either WT apoA-I or apoA-I(M).WT apoA-I- or apoA-I(M)-expressing mice were intraperitoneally injected with [H(3)]cholesterol-labeled J774 mouse macrophages. After 48 hours, no significant difference was detected in the amount of cholesterol removed from the macrophages and deposited in the feces via the RCT pathway between the WT apoA-I and apoA-I(M) groups. Analysis of the individual components of the RCT pathway demonstrated that the apoA-I(M)-expressing mice promoted ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux as efficiently as WT apoA-I but that apoA-I(M) had a reduced ability to promote cholesterol esterification via lecithin cholesterol-acyltransferase (LCAT). This resulted in reduced cholesteryl ester (CE) and increased free cholesterol (FC) levels in the plasma of mice expressing apoA-I(M) compared to WT apoA-I. These differences did not affect the rate of delivery of labeled cholesterol to the liver via SR-BI-mediated selective uptake or its subsequent excretion in the feces.Within the limits of the in vivo assay, WT apoA-I and apoA-I(M) are equally efficient at promoting macrophage RCT, suggesting that if apoA-I(M) is more atheroprotective than WT apoA-I it is not attributable to an enhancement of macrophage RCT.

SUBMITTER: Alexander ET

PROVIDER: S-EPMC2943867 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Macrophage reverse cholesterol transport in mice expressing ApoA-I Milano.

Alexander Eric T ET Weibel Ginny L GL Joshi Michelle R MR Vedhachalam Charulatha C de la Llera-Moya Margarita M Rothblat George H GH Phillips Michael C MC Rader Daniel J DJ

Arteriosclerosis, thrombosis, and vascular biology 20090806 10

<h4>Objective</h4>To compare the abilities of human wild-type apoA-I (WT apoA-I) and human apoA-I(Milano) (apoA-I(M)) to promote macrophage reverse cholesterol transport (RCT) in apoA-I-null mice infected with adeno-associated virus (AAV) expressing either WT apoA-I or apoA-I(M).<h4>Methods and results</h4>WT apoA-I- or apoA-I(M)-expressing mice were intraperitoneally injected with [H(3)]cholesterol-labeled J774 mouse macrophages. After 48 hours, no significant difference was detected in the amo ...[more]

PMID: 19661486

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Project description:OBJECTIVE:Hepatic ATP binding cassette transporter A1 (ABCA1) expression is critical for maintaining plasma high-density lipoprotein (HDL) concentrations, but its role in macrophage reverse cholesterol transport and atherosclerosis is not fully understood. We investigated atherosclerosis development and reverse cholesterol transport in hepatocyte-specific ABCA1 knockout (HSKO) mice in the low-density lipoprotein (LDL) receptor KO (LDLrKO) C57BL/6 background. APPROACH AND RESULTS:Male and female LDLrKO and HSKO/LDLrKO mice were switched from chow at 8 weeks of age to an atherogenic diet (10% palm oil, 0.2% cholesterol) for 16 weeks. Chow-fed HSKO/LDLrKO mice had HDL concentrations 10% to 20% of LDLrKO mice, but similar very low-density lipoprotein and LDL concentrations. Surprisingly, HSKO/LDLrKO mice fed the atherogenic diet had significantly lower (40% to 60%) very low-density lipoprotein, LDL, and HDL concentrations (50%) compared with LDLrKO mice. Aortic surface lesion area and cholesterol content were similar for both genotypes of mice, but aortic root intimal area was significantly lower (20% to 40%) in HSKO/LDLrKO mice. Although macrophage (3)H-cholesterol efflux to apoB lipoprotein-depleted plasma was 24% lower for atherogenic diet-fed HSKO/LDLrKO versus LDLrKO mice, variation in percentage efflux among individual mice was <2-fold compared with a 10-fold variation in plasma HDL concentrations, suggesting that HDL levels, per se, were not the primary determinant of plasma efflux capacity. In vivo reverse cholesterol transport, resident peritoneal macrophage sterol content, biliary lipid composition, and fecal cholesterol mass were similar between both genotypes of mice. CONCLUSIONS:The markedly reduced plasma HDL pool in HSKO/LDLrKO mice is sufficient to maintain macrophage reverse cholesterol transport, which, along with reduced plasma very low-density lipoprotein and LDL concentrations, prevented the expected increase in atherosclerosis.

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Macrophage reverse cholesterol transport in mice expressing ApoA-I Milano.

Publications

Macrophage reverse cholesterol transport in mice expressing ApoA-I Milano.

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