In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1 |
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Authors: | Adriaan G. Holleboom Lily Jakulj Remco Franssen Julie Decaris Menno Vergeer Joris Koetsveld Jayraz Luchoomun Alexander Glass Marc K. Hellerstein John J. P. Kastelein G. Kees Hovingh Jan Albert Kuivenhoven Albert K. Groen Scott M. Turner Erik S. G. Stroes |
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Affiliation: | 2. KineMed Inc., Emeryville, CA;4. Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Francisco, San Francisco, CA; and;11. Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, Groningen, The Netherlands |
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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 fluxes 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 13C2-cholesterol (13C-C). Enrichment of plasma and erythrocyte free cholesterol and plasma cholesterol esters was measured. With a three-compartment SAAM-II model, tissue cholesterol efflux (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 13C recovery and sterol excretion 7 days postinfusion did not differ significantly 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 efflux 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 significantly. |
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Keywords: | reverse cholesterol transport high density lipoprotein genetics fecal sterol excretion |
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