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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2960.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Estrogen Increases Apolipoprotein (Apo) A-I Secretion in Hep G2 Cells by Modulating Transcription of the Apo A-I Gene Promoter

Stefania Lamon-Fava; Jose M. Ordovas; Ernst J. Schaefer

From the Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Mass.

Correspondence to Stefania Lamon-Fava, MD, PhD, Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research, Center on Aging, Tufts University, 711 Washington St, Boston, MA 02111. E-mail sfava{at}hnrc.tufts.edu

Abstract—Estrogen administration to postmenopausal women has been shown to increase plasma levels of apolipoprotein (apo) A-I. A human hepatoma cell line, Hep G2, was used to test the hypothesis that estrogen increases the hepatic production of apo A-I by modulating gene expression. When Hep G2 cells were treated for 24 hours with E₂, the apo A-I content in the medium increased 4.3±1.0-fold at 10 µmol/L E₂ and 1.8±0.4-fold at 1 µmol/L E₂ compared with untreated cells. A time-course experiment indicated that there was no E₂-dependent (10 µmol/L) increase in apo A-I medium content at 1 hour and 2 hours and that apo A-I was 165% of controls at 6 hours and 440% at 24 hours. Hep G2 cells were transfected, by the cationic lipid method, with constructs containing serial deletions of the 5' region of the apo A-I gene (-41/+397, -256/+397, and -2500/+397) cloned in front of the luciferase gene and with or without a 7-kb region spanning the apo C-III/A-IV intergenic region, which has been shown to contain regulatory elements for the expression of the apo A-I gene. With the exception of the construct containing only the basal promoter (-41/+397), the expression of all constructs was 2- to 3-fold greater in the presence of E₂. The smallest construct that maintained E₂ responsiveness, the -256/+397 construct, does not contain a typical estrogen-responsive element. In the same transfection experiments, the 4-fold increase in apo A-I in the culture medium was preserved. However, when the same set of transfections was performed by the calcium phosphate precipitation method, the E₂ effect on the apo A-I content in the culture medium and on transcription activation was nearly abolished. This effect was probably mediated by Ca²⁺, because incubation of cells with 20 mmol/L CaCl₂ abolished the E₂ response. In conclusion, E₂ increases apo A-I production in hepatic cells by increasing the transcription of the apo A-I gene.

Key Words: 17ß-estradiol • estrogen receptor • apolipoprotein A-I

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