Transcription factors and age-related decline in apolipoprotein A-I expression.
Apolipoprotein (apo)A-I alone or as a component of high density lipoprotein particles has antiatherogenic properties. The age-dependent decline in abundance of this protein may underlie the higher risk for developing occlusive coronary artery disease (CAD) in older individuals. Similar to humans, expression of rat apoA-I also declines with age. Results in rats showed that levels of serum apoA-I protein, hepatic mRNA, and transcription of the gene were decreased to 39%, 18%, and 38%, respectively, in 180-day-old animals compared to those of newborn rats. These findings suggest that a nuclear mechanism(s) may account for the decline in apoA-I expression. Accordingly, we examined hepatic nuclear binding activity to four specific cis-acting elements of the rat apoA-I promoter. There were age-dependent changes of binding activity to two proximal sites, B and C, but not to the more distal elements, IRCE and A. Decreased B-site binding activity correlated with lower mRNA levels encoding the activator, HNF-3beta. The age-dependent change in the pattern of binding to site C was due to a switch from the activator, HNF-4, to the repressor, ARP-1. In summary, the age-related decline in apoA-I expression may arise from a reduction in the activity of both cis-acting elements, B and C.
Nakamura
T
T
Departments of Medicine and Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada, T2N 4N1.
Fox-Robichaud
A
A
Kikkawa
R
R
Kashiwagi
A
A
Kojima
H
H
Fujimiya
M
M
Wong
N C
NC
D000375:Aging / Q000097:blood / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D016632:Apolipoprotein A-I / Q000097:blood* / Q000235:genetics*; D001161:Arteriosclerosis / Q000517:prevention & control; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D003327:Coronary Disease / Q000209:etiology; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D051541:Hepatocyte Nuclear Factor 3-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D051543:Hepatocyte Nuclear Factor 3-gamma; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D016632:Apolipoprotein A-I; D017931:DNA Primers; D004268:DNA-Binding Proteins; C496499:FOXA1 protein, human; C496502:FOXA2 protein, human; C496505:FOXA3 protein, human; C496501:Foxa1 protein, rat; C496504:Foxa2 protein, rat; C496507:Foxa3 protein, rat; D051541:Hepatocyte Nuclear Factor 3-alpha; D008077:Lipoproteins, LDL; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D051543:Hepatocyte Nuclear Factor 3-gamma; D051542:Hepatocyte Nuclear Factor 3-beta