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

Abstract

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 [ 3 H]leucine into apoA-I; (3) selective increase in [ 3 H]leucine incorporation into lipoprotein (LP) A-I but not LP A-IϩA-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. (Arterioscler Thromb Vasc Biol. 1998;18:999-1006.) Key Words: estrogen Ⅲ high density lipoproteins Ⅲ apolipoprotein A-I Ⅲ cardiovascular disease A therosclerotic cardiovascular disease is the leading cause of mortality among postmenopausal women. Abnormalities in lipid and lipoprotein metabolism (eg, increased LDL and decreased HDL levels) commonly seen in postmenopausal women have been attributed to the increased coronary heart disease-related mortality in these individuals.1-3 Because the decline in estrogen levels is the primary metabolic alteration observed in postmenopausal women, it has been thought that endogenous concentrations of estrogen may have fundamental roles in lipoprotein-mediated development of atherosclerotic coronary heart disease. Clinical studies have indicated that estrogen therapy significantly elevated plasma HDL levels and decreased LDL concentrations, suggesting a favorable effect on the plasma lipoprotein profile. 4 -6 Recent comparative studies by meta-analysis showed that postmenopausal women on estrogen therapy have a lower relative risk of coronary events than postmenopausal women who are not on estrogen therapy. 7,8 Immunoaffinity techniques have revealed that HDL particles exist in 2 major classes: LP A-I and LP A-IϩA-II (ie, without and with apoA-II, respectively).9 ApoA-I and apoA-II are major proteins of HDL. There is considerable evidence to suggest that LP A-I is more importantly linked to decreased atherosclerosis risk. Premenopausal women have higher levels of LP A-I than age-matched men. 10 Oral estrogen replacement therapy in postmenopausal women was sho...

Biphasic Effects of the Natural Estrogen 17β-Estradiol on Hepatic Cholesterol Metabolism in Intact Female Rats

“…The hepatic apo A-I mRNA levels were not significantly increased at the lowest dose but displayed a clear dose-dependent relationship throughout all E2 concentrations. These findings are in agreement with previous work in vitro 38 and clearly also indicate that the variation of E2 levels within the physiological range influences plasma apo A-I and HDL cholesterol. Thus, the higher HDL cholesterol levels in female compared with male rats 7 are probably determined by their higher endogenous E2 levels.…”

Regulation of apoA-I gene expression

“…Our results show that the ARE site does not play a role in the modulation of apoA-I gene expression by estrogen and genistein, as indicated by a lack or response of the plasmid construct containing two ARE sites and the positive estrogenic response of plasmids not containing the ARE site (Ϫ256[⌬Ϫ148/ Ϫ42]A-I.Luc). In addition, our results showing a significant increase in apoA-I concentration in the media and in the A-I transcription activation following treatment with estradiol, while in contrast to the findings of Zhang et al (23), are clearly in agreement with previous studies (16,17,34).…”

“…We (16) and others (17) have previously shown that estrogen increases apoA-I gene transcription in liver cells in accordance with the results of clinical metabolic studies. We have also shown that genistein increases apoA-I transcription in liver cells (18).…”

Niacin, but Not Gemfibrozil, Selectively Increases LP-AI, a Cardioprotective Subfraction of HDL, in Patients With Low HDL Cholesterol

“…22 Using human hepatoblastoma cells, we have shown that estradiol selectively stimulates the synthesis of LP-AI particles. 23 Although niacin is the most potent clinically used agent for elevating HDL-C and apoA-I levels in dyslipidemic patients (see review 24 ), the effect of niacin on plasma levels of LP-AI and LP-AIϩAII is not established. In the present study, using a multicenter double-blind randomized design, we have examined the effect of niacin-ER versus gemfibrozil on plasma levels of LP-AI and LP-AIϩAII particles in patients with low HDL-C.…”