Inhibition of apolipoprotein A-I gene by the aryl hydrocarbon receptor: a potential mechanism for smoking-associated hypoalphalipoproteinemia.
OBJECTIVE
Smokers have lower plasma concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) compared with nonsmokers. To determine the molecular basis of this observation, the effect of activation of the aryl hydrocarbon receptor (AhR) on apo A-I gene expression was examined.


METHODS
HepG2 cells were treated with AhR receptor agonists benzo(a)pyrene (BaP) and CAY10465, and AhR receptor antagonist CAY10464 and apo A-I protein, mRNA levels and promoter activity were measured. The effect of nicotine on apo A-I protein secretion was also tested. Using a series or apo A-I gene promoter deletion constructs, a xenobiotic response element (XRE) was identified.


RESULTS
Treatment of HepG2 cells with the AhR receptor agonists BaP and CAY10465, inhibited apo A-I protein synthesis while nicotine, which does not bind AhR had no effect. Benzo(a)pyrene treatment also suppressed apo A-I mRNA and gene promoter activity. Treatment of HepG2 cells with the AhR receptor antagonist CAY10464 reversed the suppressive effect of BaP on apo A-I gene expression. A putative xenobiotic response element (XRE) was identified between nucleotides -325 and -186 (relative to the transcriptional start site, +1).


CONCLUSIONS
These results suggest that the cigarette smoking related environmental contaminant BaP promotes hypoalphalipoproteinemia in part through activation of the hepatic AhR.
Department of Medicine, University of Florida, Jacksonville College of Medicine, Jacksonville, FL, USA.
Emad
E
Naem
Rosalyn
R
Alcalde
Margaret
M
Gladysz
Sandra
S
Mesliniene
Sarada
S
Jaimungal
Mae
M
Sheikh-Ali
Michael J
MJ
Haas
Norman C W
NC
Wong
Arshag D
AD
Mooradian
D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D001580:Benzopyrenes / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000209:etiology*; D009538:Nicotine / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*
D016632:Apolipoprotein A-I; D001580:Benzopyrenes; D018336:Receptors, Aryl Hydrocarbon; D009538:Nicotine