Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL.
HDL promotes cholesterol efflux from peripheral cells via 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 apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism 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 the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL.
Soro-Paavonen
Aino
A
Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
Naukkarinen
Jussi
J
Lee-Rueckert
Miriam
M
Watanabe
Hiroshi
H
Rantala
Elina
E
Soderlund
Sanni
S
Hiukka
Anne
A
Kovanen
Petri T
PT
Jauhiainen
Matti
M
Peltonen
Leena
L
Taskinen
Marja-Riitta
MR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007009:Hypolipoproteinemias / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D002784:Cholesterol