AIMS: 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. MAIN 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. KEY FINDINGS: 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). SIGNIFICANCE: These results suggest that the cigarette smoking related environmental contaminant BaP promotes hypoalphalipoproteinemia in part through activation of the hepatic AhR.
AIMS: 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. MAIN 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. KEY FINDINGS: 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). SIGNIFICANCE: These results suggest that the cigarette smoking related environmental contaminant BaP promotes hypoalphalipoproteinemia in part through activation of the hepatic AhR.