© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Biphasic Effects of the Natural Estrogen 17ß-Estradiol on Hepatic Cholesterol Metabolism in Intact Female Rats
From the Metabolism Unit (P.P., B.A., B.F., M.R.), Center for Metabolism and Endocrinology, Department of Medicine, and the Molecular Nutrition Unit, Center for Nutrition and Toxicology Novum, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden; and the Division of Reproductive Endocrinology (A.S-E., B.F., H.E.), Department of Woman and Child Health, Karolinska Institute at Karolinska Hospital, Stockholm, Sweden.
Correspondence to Paolo Parini, MD, PhD, CME, M63, Huddinge University Hospital, S-141 86 Stockholm, Sweden. E-mail paolo.parini{at}cnt.ki.se
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 17ß-estradiol
(E2) administered either subcutaneously or orally. After
physiological doses of E2 (
0.04 mg ·
kg-1 · d-1) 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 (
0.2 mg ·
kg-1 · d-1), 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 • bile acids • lipoproteins • LDL receptors • estrogen receptors
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