In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1

Abstract

This article is available online at http://www.jlr.org Supplementary key words reverse cholesterol transport • high density lipoprotein • genetics • fecal sterol excretionEpidemiological studies have demonstrated a strong inverse relationship between plasma high density lipoprotein cholesterol (HDL-c) concentrations and the risk of cardiovascular disease ( 1-4 ). However, the anti-atherogenic properties of HDL could not be substantiated in a recent meta-regression analysis: pharmacological increases in HDL-c did not translate into a decreased cardiovascular disease risk ( 5 ). These fi ndings have emphasized the need for other measures than plasma HDL-c concentrations to assess the atheroprotective properties of HDL. Ideally, such measures should relate directly to the mechanistic pathways that form the basis of the proposed anti-atherogenic effects of HDL in humans ( 3, 6 ).The most frequently studied function of HDL is its role in the reverse transport of cholesterol from peripheral tissues (RCT). RCT has been proposed as the uptake of cholesterol from peripheral cells by nascent HDL particles mainly consisting of lipid-poor apolipoprotein A-I (apoA-I), mediated by lipid transporter molecules such as ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) and scavenger receptor type B-I (SR-BI) and the subsequent Abstract Atheroprotection by high density lipoprotein (HDL) is considered to be mediated through reverse cholesterol transport (RCT) from peripheral tissues. We investigated in vivo cholesterol fl uxes through the RCT pathway in patients with low plasma high density lipoprotein cholesterol (HDL-c) due to mutations in APOA1 . Seven carriers of the L202P mutation in APOA1 (mean HDL-c: 20 ± 19 mg/dl) and seven unaffected controls (mean HDL-c: 54 ± 11 mg/dl, P < 0.0001) received a 20 h infusion of 13 C 2 -cholesterol ( 13 C-C). Enrichment of plasma and erythrocyte free cholesterol and plasma cholesterol esters was measured. With a threecompartment SAAM-II model, tissue cholesterol effl ux (TCE) was calculated. TCE was reduced by 19% in carriers (4.6 ± 0.8 mg/kg/h versus 5.7 ± 0.7 mg/kg/h in controls, P = 0.02). Fecal 13 C recovery and sterol excretion 7 days postinfusion did not differ signifi cantly between carriers and controls: 21.3 ± 20% versus 13.3 ± 6.3% ( P = 0.33), and 2,015 ± 1,431 mg/day versus 1456 ± 404 mg/day ( P = 0.43), respectively. TCE is reduced in carriers of mutations in APOA1 , suggesting that HDL contributes to effl ux of tissue cholesterol in humans. The residual TCE and unaffected fecal sterol excretion in our severely affected carriers suggest, however, that non-HDL pathways contribute to RCT signifi cantly. -Holleboom, A.

Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA

“…is supported by epidemiological studies showing the steepest association between CVD risk and HDL-c levels in patients with markedly lowered HDL-c levels ( 2, 3 ). More recently, we substantiated the impact of low HDL-c on tissue cholesterol efflux, particularly in patients with very low HDL-c levels ( 9 ), which is compatible with the concept that the best therapeutic result of apoA-I infusion can be obtained in those patients with the lowest apoA-I levels. As the limited number of subjects included in the present study does not allow for subgroup analysis, further studies are needed to determine to what extent the response to apoA-I treatment depends upon the baseline apoA-I levels and/or baseline genotype.…”

“…apoA-I has been shown to play a key role in the initial step of reverse cholesterol transport (RCT) ( 7,8 ). Tissue cholesterol effl ux was decreased in patients with the orphan disease of genetically-determined low HDL-c, familial hypoalphalipoproteinemia (FHA) ( 9 ), which coincided with accelerated atherogenesis ( 10,11 ). Early results from infusion experiments with reconstituted HDL corroborated a therapeutic potential, showing increased fecal cholesterol excretion ( 12,13 ), as well as a reduction in the cholesterol content in human atherosclerotic lesions ( 14 ).…”

HDL and atherosclerosis: Insights from inherited HDL disorders

“…The striking difference in preclinical atherosclerosis between carriers of two missense mutations in the APOA1 gene, both leading to similar plasma HDL-C and apoA-I reductions [9,73], is likely due to the different effects of the two mutations on the protein and HDL structure. The A-I M variant contains a cysteine, which allows the formation of dimers with a prolonged half-life [74], and circulates in plasma in small HDL particles with enhanced cellular cholesterol efflux capacity [53], while the apoA-I(L202P) is associated with reduced in vivo tissue cholesterol efflux [75].…”

Cholesterol Efflux and Atheroprotection

“…Coefficient of variation of the measurement was 10–15% in humans. The consequences of hypoalphalipoprotemia due to ABCAI or ApoAI genetic alterations were explored in a Dutch population (141). Among low HDL-C participants, there was ~40% reduction in efflux despite normal esterification and fecal excretion rates.…”