Regulation of apolipoprotein A-I gene expression: mechanism of action of estrogen and genistein

doi:10.1194/jlr.M300179-JLR200

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Regulation of apolipoprotein A-I gene expression: mechanism of action of estrogen and genistein

Stefania Lamon-Fava and Dale Micherone

Lipid Metabolism Laboratory, Tufts University, Boston, MA 02111

Corresponding Author: stefania.lamon-fava{at}tufts.edu

We have previously shown that 17-beta-estradiol (E2) and genistein increase the secretion of apolipoprotein (apo) A-I, the major protein component of high-density lipoproteins, in Hep G2 cells by increasing the transcription of the apo A-I gene. The aim of this study was to elucidate the mechanism mediating the increase in apo A-I gene expression by these compounds. A series of plasmid constructs containing serial deletions of the apo A-I promoter region was generated. The –220 to –148 region of the apo A-I promoter was the smallest region maintaining response to E2 and genistein, and the estrogen antagonist ICI 182,780 completely inhibited the E2 and genistein effect. This region contains a binding site for transcription factors belonging to the steroid/thyroid nuclear receptor superfamily (site A), a binding site for HNF-3b (site B), and two binding sites for Egr-1. Nuclear extracts from cells treated with E2 and genistein showed increased binding to site B and nuclear extracts from genistein-treated cells showed increased binding to Egr-1 oligonucleotide, compared to control cells. An increase in the concentrations of Egr-1 and HNF-3b was observed in nuclear extracts of cells treated with E2 and genistein, compared to control cells. Treatment of Hep G2 cells with a specific inhibitor of MAP kinase, but not with other inhibitors, abolished the stimulation of apo A-I gene expression by E2 and genistein. These results indicate that the MAP kinase pathway is involved in the regulation of apo A-I gene expression by genistein and E2, possibly through downstream regulation of transcription factors binding to the promoter region.

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