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This version published online on June 22, 2006
Endocrinology, doi:10.1210/en.2006-0116
A more recent version of this article appeared on September 1, 2006
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Submitted on January 27, 2006
Accepted on June 9, 2006

MOUSE STEROL RESPONSE ELEMENT BINDING PROTEIN (SREBP)-1c GENE EXPRESSION IS NEGATIVELY REGULATED BY THYROID HORMONE

Koshi Hashimoto*, Masanobu Yamada, Shunichi Matsumoto, Tsuyoshi Monden, Teturou Satoh, and Masatomo Mori

Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan 371-8511

* To whom correspondence should be addressed. E-mail: khashi{at}med.gunma-u.ac.jp.

Sterol regulatory element-binding protein (SREBP)-1c is a key regulator of fatty acid metabolism and plays a pivotal role in the transcriptional regulation of different lipogenic genes mediating lipid synthesis. In previous studies, the regulation of SREBP-1c mRNA levels by thyroid hormone has remained controversial. In this study, we examined whether triiodothyronine (T3) regulates the mouse SREBP-1c mRNA expression. We found that T3 negatively regulates the mouse SREBP-1c gene expression in the liver, as shown by RNase protection assays and real-time quantitative RT (RT)-PCR. Promoter analysis with luciferase assays using HepG2 and Hepa1-6 cells revealed that T3 negatively regulates the mouse SREBP-1c gene promoter (-574 to +42) and that Site2 (GCCTGACAGGTGAAATCGGC) located around the transcriptional start site is responsible for the negative regulation by T3. Gel shift assays showed that retinoid X receptor (RXR)-{alpha} / thyroid hormone receptor (TR)-{beta} heterodimer bound to Site2 but RXR-{alpha} / liver X receptor (LXR)- {alpha} heterodimer could not bind to the site. In vivo chromatin immunoprecipitation (ChIP) assays demonstrated that T3 induced TR-{beta} recruitment to Site2. Thus, we demonstrated that mouse SREBP-1c mRNA is down-regulated by T3 in vivo and that T3 negatively regulates mouse SREBP-1c gene transcription via a novel negative thyroid hormone response element:Site2.
Key words: SREBP-1c • thyroid hormone




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