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

Abstract

Abstract-The protective influence of estrogens in cardiovascular disease is believed to be partly due to beneficial effects on cholesterol metabolism. Much of the experimental data are based on models in which synthetic estrogens have been used in pharmacological doses, and therefore, the physiological role of estrogens in cholesterol metabolism is uncertain.To evaluate this important issue, we performed experiments in intact female rats with use of the natural estrogen 17␤-estradiol (E2) administered either subcutaneously or orally. After physiological doses of E2 (Յ0.04 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) were administered, plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I were increased. In the liver, 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7␣-hydroxylase activities were increased, as well as cholesterol 7␣-hydroxylase mRNA levels. These effects were abolished during treatment with higher doses of E2, whereas apo A-I mRNA increased in a dose-dependent way. After treatment with pharmacological doses of E2 (Ն0.2 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ), the number of hepatic low density lipoprotein receptors increased and plasma cholesterol was reduced. These effects were similar after both oral and subcutaneous administration of E2. Our results show that the responses to E2 are biphasic: plasma HDL, apo A-I, and hepatic enzyme activities governing bile acid and cholesterol synthesis increased only at physiological doses of E2. At pharmacological doses of E2, hepatic low density lipoprotein receptors are stimulated and plasma cholesterol is reduced. Therefore, under physiological conditions, E2 exerts its major effects on hepatic cholesterol metabolism through mechanisms other than stimulation of low density lipoprotein receptor expression. Key Words: apolipoprotein A-I Ⅲ bile acids Ⅲ lipoproteins Ⅲ LDL receptors Ⅲ estrogen receptors E ndogenous sex steroids are believed to protect premenopausal women against the development of coronary heart disease. 1,2 Estrogens have been reported to have a number of potentially beneficial effects on lipoprotein metabolism, resulting in reduced LDL and increased HDL cholesterol in plasma. [1][2][3][4][5] Attempts to identify the mechanisms by which endogenous estrogens modulate their effects in vivo are hampered by the difficulty of interpreting data from experimental models. Thus, the varying effects observed may be related to species, sex, and initial hormonal status (eg, postmenopausal or ovariectomized versus fertile). Differences in dose and efficiency between estrogen preparations, as well as the mode of administration (eg, oral versus parenteral), may also be important.Much of our knowledge of estrogen's effects on lipoprotein metabolism is based on studies in rats. In this species, the plasma total and HDL cholesterol levels are higher in females than in males. 6,7 High doses of estrogens (1 to 5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 of ethynyl estradiol) reduce plasma cholesterol levels in male rats. 8 This effect is in part caused by increased elimination of ...

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

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Hormonal and metabolic effects of genistein and daidzein in male rat

“…This hormone may influence not only cholesterol elimination but also its metabolism. These effects depends, however, on its concentration (Parini et al, 2000). The literature data provide evidence that consumption of diets containing soya protein (and phytooestrogens which are tightly associated with proteins) reduces total cholesterol and LDL-cholesterol (Carroll, 1991) and augments HDL-cholesterol (Anthony et al, 1996).…”

Estrogen receptor 2 and progesterone receptor gene polymorphisms and lipid levels in women with different hormonal status

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