ESTRADIOL STIMULATES APOLIPOPROTEIN A-I-CONTAINING BUT NOT A-II-CONTAINING PARTICLE SYNTHESIS AND SECRETION BY STIMULATING MESSENGER-RNA TRANSCRIPTION RATE IN HEP G2 CELLS

Estrogen therapy increases plasma HDL levels, which may reduce cardiov ascular risk in postmenopausal women. The mechanism of action of estro gen in influencing various steps in hepatic HDL and apolipoprotein (ap o) 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 vi tro model system to delineate the effect of estradiol on multiple regu latory steps involved in hepatic HDL metabolism. Incubation of Hep G2 cells with estradiol resulted in the following statistically significa nt findings: (1) increased accumulation of apoA-I in the medium withou t affecting uptake/removal of radiolabeled HDL-protein; (2) accelerate d incorporation of [H-3]leucine into apoA-I; (3) selective increase in [H-3]leucine incorporation into lipoprotein (LP) A-I but not LP A-I+A -II HDL particles (HDL particles without and with apoA-II, respectivel y); (4) increased ability of apoA-I-containing particles to efflux cho lesterol from fibroblasts; (5) stimulated steady state apoA-I but not apoA-II mRNA expression; and (6) increased newly transcribed apoA-I mR NA message without effect on apoA-I mRNA half-life. The data indicate that estradiol stimulates newly transcribed hepatic apoA-I mRNA, resul ting in a selective increase in LP A-I, a subfraction of HDL that is a ssociated with decreased atherosclerotic cardiovascular disease, espec ially in premenopausal women.