Abstract 17881: In vivo Tissue Cholesterol Efflux is Impaired in Carriers of Mutations in APOA1 and ABCA1
Background: Reverse cholesterol transport from peripheral tissues to the liver (RCT) is considered the main atheroprotective mechanism of high density lipoprotein (HDL). Although individual stages of RCT have been studied in detail in experimental models, solid data on cholesterol flux through the entire RCT pathway and its dependency on plasma HDL-cholesterol (HDL-c) levels in humans is absent. In the present study we applied an isotope dilution protocol to assess whole-body tissue cholesterol efflux in patients with familial hypoalphalipoproteinemia versus healthy, matched controls.
Methods and Results: To study tissue cholesterol efflux (TCE) in vivo, 5 carriers of a mutation in APOA1, 2 patients homozygous for a mutation in ABCA1 (mean HDL-c: 12.8 ± 13 mg/dl) and 6 unaffected controls (mean HDL-c: 54.9 ± 11 mg/dl, p<0.0001)) received a 20 hour constant infusion of 13C2-cholesterol (13C2-C). Cholesterol efflux from peripheral tissues into plasma was calculated as the dilution flux decreasing plasma 13C2-C. To calculate the cholesterol fluxes, a 3-compartment SAAM II fit was applied to plasma free cholesterol, cholesterol ester and erythrocyte enrichment profiles. TCE was on average 38% reduced in carriers compared to controls (3.22 ± 1.21 mg/kg/hr versus 5.14 ± 0.74 mg/kg/hr, p<0.01) and was significantly correlated with HDL-c levels (Pearson's R=0.57; p<0.05). By contrast, fecal 13C2-C recovery and total fecal sterol excretion were comparable in carriers and controls (9.9 ± 6.2% versus 11.9 ± 5.6% and 1429 ± 899 mg/day versus 1562 ± 578 mg/day (both n.s.), respectively).
Conclusions: In vivo tissue cholesterol efflux is impaired in carriers of mutations in ABCA1 or APOA1. Fecal sterol excretion however, was comparable to unaffected controls. These data lend strong support to the concept that HDL drives tissue cholesterol efflux in humans, whereas fecal sterol excretion may also depend on non-HDL mediated pathways.
- © 2010 by American Heart Association, Inc.