ANDROGEN RECEPTOR-MEDIATED ANTAGONISM OF ESTROGEN-DEPENDENT LOW-DENSITY-LIPOPROTEIN RECEPTOR TRANSCRIPTION IN CULTURED-HEPATOCYTES

Postmenopausal women receiving hormone replacement therapy have a lowe r risk of coronary heart disease than women who do not receive hormone treatment. Multiple mechanisms are likely to underlie estrogen's card ioprotective action, including lowering of plasma low density lipoprot ein (LDL) cholesterol. Using an in vitro system exhibiting normal regu lation of LDL receptor (LDLR) gene transcription, we show that 17 beta -estradiol activates the LDLR promoter in transiently transfected HepG 2 cells. LDLR activation by estrogen in HepG2 cells is dependent on th e presence of exogenous estrogen receptor, and the estrogen-responsive region of the LDLR promoter colocalizes with the sterol response elem ent previously identified. The estrogen response is concentration depe ndent, saturable, and sensitive to antagonism by estrogen receptor ant agonists. Further, we show that compounds with androgen receptor agoni st activity attenuate the estrogen-induced up-regulation of LDLR in ou r model system. Progestins with androgen receptor agonist activity, su ch as medroxyprogesterone acetate, also suppress estrogen's effects on LDLR expression through their androgenic properties. Characterization of the interplay between these hormone receptors on the LDLR in vitro system may allow a better understanding of the actions of sex steroid s on LDLR gene expression and their roles in cardiovascular disease.