Importance of estrogen receptors in hepatic LDL receptor regulation

Treatment with pharmacological doses of estrogen is the most potent way to stimulate hepatic LDL receptor expression in vivo. The mechanism for this effect is unclear, in part because of difficulties in inducing this stimulation in vitro. A fundamental question, whether estrogen receptors (ERs) mediate this stimulation, has not been addressed. The aim of the current study was to determine the involvement of ERs in the estrogen-induced stimulation of LDL receptors. Treatment of rats with high doses of ethynylestradiol for 7 days increased the hepatic LDL receptor protein and mRNA levels four- and threefold, respectively. LDL receptor stimulation in estrogen-treated rats was not due to their reduced food intake because hepatic LDL receptor expression did not increase in rats fasted for 72 hours. Treatment with antiestrogen (tamoxifen or clomiphene) abolished the LDL receptor stimulatory effect of ethynylestradiol at both the protein and mRNA levels. Antiestrogen alone had no effect on hepatic LDL receptor expression and did not influence the strong resistance to dietary cholesterol normally present in rats. It is concluded that ERs are critically involved in the induction of hepatic LDL receptor expression by ethynylestradiol. The known role of growth hormone for the expression of hepatic ERs may therefore play a role in the modulation of the effects of estrogen on cholesterol metabolism and hepatic LDL receptors in the rat.