HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 1, 295-302, January 6, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/1/295    most recent M507877200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hashimoto, K. Articles by Wondisford, F. E. Search for Related Content PubMed PubMed Citation Articles by Hashimoto, K. Articles by Wondisford, F. E. Social Bookmarking                      What's this?

Cross-talk between Thyroid Hormone Receptor and Liver X Receptor Regulatory Pathways Is Revealed in a Thyroid Hormone Resistance Mouse Model^*

Koshi Hashimoto, Ronald N. Cohen, Masanobu Yamada, Kathleen R. Markan, Tsuyoshi Monden, Teturou Satoh, Masatomo Mori, and Fredric E. Wondisford1

From the Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan and the Department of Medicine, Section of Endocrinology and Committee on Molecular Metabolism and Nutrition, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637

Hypercholesterolemia is found in patients with hypothyroidism and resistance to thyroid hormone. In this study, we examined cholesterol metabolism in a thyroid hormone receptor (TR-) mutant mouse model of resistance to thyroid hormone. Whereas studies of cholesterol metabolism have been reported in TR- knock-out mice, generalized expression of a non-ligand binding TR- protein in this knock-in model more fully recapitulates the hypothyroid state, because the hypothyroid effect of TRs is mediated by the unliganded receptor. In the hypothyroid state, a high cholesterol diet increased serum cholesterol levels in wild-type animals (WT) but either did not change or reduced levels in mutant (MUT) mice relative to hypothyroidism alone. 7-Hydroxylase (CYP7A1) is the rate-limiting enzyme in cholesterol metabolism and mRNA levels were undetectable in the hypothyroid state in all animals. triiodothyronine replacement restored CYP7A1 mRNA levels in WT mice but had minimal effect in MUT mice. In contrast, a high cholesterol diet markedly induced CYP7A1 levels in MUT but not WT mice in the hypothyroid state. Elevation of CYP7A1 mRNA levels and reduced hepatic cholesterol content in MUT animals are likely because of cross-talk between TR- and liver X receptor (LXR-), which both bind to a direct repeat + 4(DR+4) element in the CYP7A1 promoter. In transfection studies, WT but not MUT TR- antagonized induction of this promoter by LXR-. Electromobility shift analysis revealed that LXR/RXR heterodimers bound to the DR+4 element in the presence of MUT but not WT TR-. A mechanism for cross-talk, and potential antagonism, between TR- and LXR- is proposed.

Received for publication, July 20, 2005 , and in revised form, October 28, 2005.

^* This work was supported by National Institutes of Health Grants DK 49126 and DK 53036 (to F. E. W.) and a grant from the Ministry of Health and Welfare of Japan for Research on Measures for Intractable Diseases (to M. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom all correspondence should be addressed: Metabolism Division, Dept. of Pediatrics and Medicine, Johns Hopkins Medical Institute, 600 N. Wolfe St., Park 211, Baltimore, MD 21287. Tel.: 410-955-6463; Fax: 410-955-9773; E-mail: fwondisford{at}jhmi.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. Hashimoto, E. Ishida, S. Matsumoto, S. Okada, M. Yamada, T. Satoh, T. Monden, and M. Mori Carbohydrate Response Element Binding Protein Gene Expression Is Positively Regulated by Thyroid Hormone Endocrinology, July 1, 2009; 150(7): 3417 - 3424. [Abstract] [Full Text] [PDF]

				S. Matsumoto, K. Hashimoto, M. Yamada, T. Satoh, J. Hirato, and M. Mori Liver X Receptor-{alpha} Regulates Proopiomelanocortin (POMC) Gene Transcription in the Pituitary Mol. Endocrinol., January 1, 2009; 23(1): 47 - 60. [Abstract] [Full Text] [PDF]

				K. Hashimoto, S. Matsumoto, M. Yamada, T. Satoh, and M. Mori Liver X Receptor-{alpha} Gene Expression Is Positively Regulated by Thyroid Hormone Endocrinology, October 1, 2007; 148(10): 4667 - 4675. [Abstract] [Full Text] [PDF]

				N. E. Buroker, M. E. Young, C. Wei, K. Serikawa, M. Ge, X.-H. Ning, and M. A. Portman The dominant negative thyroid hormone receptor beta-mutant {Delta}337T alters PPAR{alpha} signaling in heart Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E453 - E460. [Abstract] [Full Text] [PDF]

				D.-J. Shin, M. Plateroti, J. Samarut, and T. F. Osborne Two uniquely arranged thyroid hormone response elements in the far upstream 5' flanking region confer direct thyroid hormone regulation to the murine cholesterol 7{alpha} hydroxylase gene Nucleic Acids Res., September 1, 2006; 34(14): 3853 - 3861. [Abstract] [Full Text] [PDF]

				K. Hashimoto, M. Yamada, S. Matsumoto, T. Monden, T. Satoh, and M. Mori Mouse Sterol Response Element Binding Protein-1c Gene Expression Is Negatively Regulated by Thyroid Hormone Endocrinology, September 1, 2006; 147(9): 4292 - 4302. [Abstract] [Full Text] [PDF]