title: Unique effect of 4-hydroxyestradiol and its methylation metabolites on lipid and cholesterol profiles in ovariectomized female rats.
abstract: 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 E2or 4-OH-E2is 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 E2or 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 E2metabolites 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.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen, Shenzhen, Guangdong 518172, China. Electronic address: BTZhu@CUHK.edu.cn.
authors.forename: Bao-Ting
authors.initials: BT
authors.lastname: Zhu
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D004435:Eating / Q000187:drug effects; D002393:Estrogens, Catechol / Q000378:metabolism* / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020738:Leptin / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors / Q000235:genetics; D008745:Methylation; D010052:Ovariectomy; D047495:PPAR gamma / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002393:Estrogens, Catechol; D020738:Leptin; D000071518:Liver X Receptors; D047495:PPAR gamma; D002784:Cholesterol; C014036:4-hydroxyestradiol; C532838:CYP7A1 protein, rat; D002790:Cholesterol 7-alpha-Hydroxylase
keywords: 4-Hydroxyestradiol; 4-Hydroxyestradiol (PubChem CID: 5282360); 4-Methoxyestradiol (PubChem CID: 68578); 4-Methoxyestrogen; 4-Methoxyestrone (PubChem CID: 194066); CYP7A1; Cholesterol; Estradiol (PubChem CID: 5757); Triglyceride