Estradiol Stimulates Apolipoprotein A-I– but Not A-II–Containing Particle Synthesis and Secretion by Stimulating mRNA Transcription Rate in Hep G2 Cells

From the Cholesterol Center, Medical Service, Long Beach (Calif) Department of Veterans Affairs Medical Center; and the University of California, Irvine.

Correspondence to Moti L. Kashyap, MD, Professor of Medicine and Pathology, Director, Cholesterol Center, Chief, Gerontology Section (111GE), Department of Veterans Affairs Medical Center, 5901 E Seventh St, Long Beach, CA 90822.

Abstract—Estrogen therapy increases plasma HDL levels, which may reduce cardiovascular risk in postmenopausal women. The mechanism of action of estrogen in influencing various steps in hepatic HDL and apolipoprotein (apo) A-I synthesis and secretion are not fully understood. In this study, we have used the human hepatoblastoma cell line (Hep G2) as an in vitro model system to delineate the effect of estradiol on multiple regulatory steps involved in hepatic HDL metabolism. Incubation of Hep G2 cells with estradiol resulted in the following statistically significant findings: (1) increased accumulation of apoA-I in the medium without affecting uptake/removal of radiolabeled HDL-protein; (2) accelerated incorporation of [³H]leucine into apoA-I; (3) selective increase in [³H]leucine incorporation into lipoprotein (LP) A-I but not LP A-I+A-II HDL particles (HDL particles without and with apoA-II, respectively); (4) increased ability of apoA-I–containing particles to efflux cholesterol from fibroblasts; (5) stimulated steady state apoA-I but not apoA-II mRNA expression; and (6) increased newly transcribed apoA-I mRNA message without effect on apoA-I mRNA half-life. The data indicate that estradiol stimulates newly transcribed hepatic apoA-I mRNA, resulting in a selective increase in LP A-I, a subfraction of HDL that is associated with decreased atherosclerotic cardiovascular disease, especially in premenopausal women.

Key Words: estrogen • high density lipoproteins • apolipoprotein A-I • cardiovascular disease

This article has been cited by other articles:

				S. Lamon-Fava, B. Postfai, M. Diffenderfer, C. DeLuca, J. O'Connor Jr, F. K. Welty, G. G. Dolnikowski, P. H. R. Barrett, and E. J. Schaefer Role of the Estrogen and Progestin in Hormonal Replacement Therapy on Apolipoprotein A-I Kinetics in Postmenopausal Women Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 385 - 391. [Abstract] [Full Text] [PDF]

				S. Lamon-Fava and D. Micherone Regulation of apoA-I gene expression: mechanism of action of estrogen and genistein J. Lipid Res., January 1, 2004; 45(1): 106 - 112. [Abstract] [Full Text] [PDF]

				R. M. Krauss Individualized Hormone-Replacement Therapy? N. Engl. J. Med., March 28, 2002; 346(13): 1017 - 1018. [Full Text] [PDF]

				X. Zhang, J.-J. Jiao, B. R. Bhavnani, and S.-P. Tam Regulation of human apolipoprotein A-I gene expression by equine estrogens J. Lipid Res., November 1, 2001; 42(11): 1789 - 1800. [Abstract] [Full Text] [PDF]

				T. Sakai, V. S. Kamanna, and M. L. Kashyap Niacin, but Not Gemfibrozil, Selectively Increases LP-AI, a Cardioprotective Subfraction of HDL, in Patients With Low HDL Cholesterol Arterioscler. Thromb. Vasc. Biol., November 1, 2001; 21(11): 1783 - 1789. [Abstract] [Full Text] [PDF]

				S. Lamon-Fava Genistein Activates Apolipoprotein A-I Gene Expression in the Human Hepatoma Cell Line Hep G2 J. Nutr., October 1, 2000; 130(10): 2489 - 2492. [Abstract] [Full Text]

				P. Parini, B. Angelin, A. Stavreus-Evers, B. Freyschuss, H. Eriksson, and M. Rudling Biphasic Effects of the Natural Estrogen 17{beta}-Estradiol on Hepatic Cholesterol Metabolism in Intact Female Rats Arterioscler. Thromb. Vasc. Biol., July 1, 2000; 20(7): 1817 - 1823. [Abstract] [Full Text] [PDF]

				S. Lamon-Fava, J. M. Ordovas, and E. J. Schaefer Estrogen Increases Apolipoprotein (Apo) A-I Secretion in Hep G2 Cells by Modulating Transcription of the Apo A-I Gene Promoter Arterioscler. Thromb. Vasc. Biol., December 1, 1999; 19(12): 2960 - 2965. [Abstract] [Full Text] [PDF]