Submitted on October 12, 2006
Revised on March 12, 2007
Accepted on March 19, 2007
Common ABCA1 variants, HDL levels and cellular cholesterol efflux in subjects with familial low-HDL
Aino Soro-Paavonen, Jussi Naukkarinen, Miriam Lee-Rueckert, Hiroshi Watanabe, Elina Rantala, Sanni Soderlund, Anne Hiukka, Petri T. Kovanen, Matti Jauhiainen, Leena Peltonen, and Marja-Riitta Taskinen
Department of Medicine, University of Helsinki, Helsinki 00290
Corresponding Author: Marja-Riitta.Taskinen{at}helsinki.fi
HDL promotes cholesterol efflux from peripheral cells via the ATP-binding cassette transporter A1 (ABCA1) in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apoA-I (as %) was measured in 22 patients with familial low HDL, without Tangier Disease (TD) mutations, and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using SNP haplotypes, and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P=0.001) lower in the low HDL group. Cholesterol-loaded macrophages from low HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL.
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