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J. Biol. Chem., Vol. 280, Issue 30, 27533-27543, July 29, 2005

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Thyroid Hormone Regulates the Hypotriglyceridemic Gene APOA5^*

Xavier Prieur, Thierry Huby, Hervé Coste, Frank G. Schaap¶, M. John Chapman, and Joan C. Rodríguez||

From the GlaxoSmithKline, 25 Avenue du Québec, 91951 Les Ulis cedex, France, ^¶AMC Liver Center, Meibergdreef 69-71, 1105 BK Amsterdam, The Netherlands, and the Dyslipoproteinemia and Atherosclerosis Research Unit (U551), National Institute for Health and Medical Research, Hôpital de la Pitié, Paris Cedex 13, France

The apolipoprotein AV gene (APOA5) is a key determinant of plasma triglyceride levels, a major risk factor for coronary artery disease and a biomarker for the metabolic syndrome. Since thyroid hormones influence very low density lipoprotein triglyceride metabolism and clinical studies have demonstrated an inverse correlation between thyroid status and plasma triglyceride levels, we examined whether APOA5 is regulated by thyroid hormone. Here we report that 3,5,3'-triiodo-L-thyronine (T₃) and a synthetic thyroid receptor (TR) ligand increase APOA5 mRNA and protein levels in hepatocytes. Our data revealed that T₃-activated TR directly regulates APOA5 promoter through a functional direct repeat separated by four nucleotides (DR4). Interestingly, we show that upstream stimulatory factor 1, a transcription factor associated with familial combined hyperlipidemia and elevated triglyceride levels in humans, and upstream stimulatory factor 2 cooperate with TR, resulting in a synergistic activation of APOA5 promoter in a ligand-dependent manner via an adjacent E-box motif. In rats, we observed that apoAV levels declines with thyroid hormone depletion but returned to normal levels upon T₃ administration. In addition, treatments with a TR-selective agonist increased apoAV and diminished triglyceride levels. The identification of APOA5 as a T₃ target gene provides a new potential mechanism whereby thyroid hormones can influence triglyceride homeostasis. Additionally, these data suggest that TR may be a potential pharmacological target for the treatment of hypertriglyceridemia.

Received for publication, March 22, 2005 , and in revised form, May 31, 2005.

^* 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.

^|| To whom correspondence should be addressed. E-mail: jcrodrig{at}freesurf.fr.

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