Androgen Receptor-Mediated Antagonism of Estrogen-Dependent Low Density Lipoprotein Receptor Transcription in Cultured Hepatocytes

Postmenopausal women receiving hormone replacement therapy have a lower risk of coronary heart disease than women who do not receive hormone treatment. Multiple mechanisms are likely to underlie estrogen’s cardioprotective action, including lowering of plasma low density lipoprotein (LDL) cholesterol. Using an in vitro system exhibiting normal regulation of LDL receptor (LDLR) gene transcription, we show that 17β-estradiol activates the LDLR promoter in transiently transfected HepG2 cells. LDLR activation by estrogen in HepG2 cells is dependent on the presence of exogenous estrogen receptor, and the estrogen-responsive region of the LDLR promoter colocalizes with the sterol response element previously identified. The estrogen response is concentration dependent, saturable, and sensitive to antagonism by estrogen receptor antagonists. Further, we show that compounds with androgen receptor agonist activity attenuate the estrogen-induced up-regulation of LDLR in our model system. Progestins with androgen rec...