Unique effect of 4-hydroxyestradiol and its methylation metabolites on lipid and cholesterol profiles in ovariectomized female rats

• Published in: European journal of pharmacology 2017-04, Vol.800, p.107-117
• Main Authors: Wang, Pan, Zhu, Bao-Ting
• Format: Article
• Language: English
• Subjects: 4-Hydroxyestradiol; 4-Methoxyestrogen; Adipose Tissue - cytology; Adipose Tissue - drug effects; Animals; Body Weight - drug effects; Cholesterol; Cholesterol - blood; Cholesterol - metabolism; Cholesterol 7-alpha-Hydroxylase - genetics; CYP7A1; Eating - drug effects; Estrogens, Catechol - metabolism; Estrogens, Catechol - pharmacology; Female; Gene Expression Regulation, Enzymologic - drug effects; Leptin - genetics; Liver - drug effects; Liver - metabolism; Liver X Receptors - genetics; Methylation; Ovariectomy; PPAR gamma - genetics; Rats; Rats, Sprague-Dawley; Triglyceride
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.02.032

Animal studies have shown that endogenous estrogens such as 17β-estradiol (E2) can modulate lipid profiles in vivo, and this effect is generally thought to be mediated by the estrogen receptors (ERs). The present study sought to test a hypothesis that some of the endogenous estrogen metabolites that have very weak estrogenic activity may exert some of their modulating effects on lipid metabolism in an ER-independent manner. Using ovariectomized female rats as an in vivo model, we found that 4-hydroxyestradiol (4-OH-E2) has a markedly stronger effect in reducing the adipocyte size and serum cholesterol level in rats compared to E2, despite the weaker estrogenic activity of 4-OH-E2. Moreover, when E2 or 4-OH-E2 is used in combination with ICI-182,780 (an ER antagonist), some of their lipid-modulating effects are not blocked by this antiestrogen. Interestingly, two of the O-methylation metabolites of 4-OH-E2, namely, 4-methoxyestradiol and 4-methoxyestrone, which have much weaker estrogenic activity, were also found to have similar lipid-modulating effects compared to 4-OH-E2. Mechanistically, up-regulation of the expression of leptin, cytochrome P450 7A1 and LXRα genes is observed in the liver of animals treated with E2 or 4-OH-E2, and the up-regulation is essentially not inhibited by co-treatment with ICI-182,780. These results demonstrate that some of the endogenous E2 metabolites are functionally important modulators of lipid metabolic profiles in vivo. In addition, our findings indicate that an ER-independent pathway likely mediates some of the lipid-modulating effects of endogenous estrogens and their metabolic derivatives.