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J. Biol. Chem., Vol. 281, Issue 17, 11553-11559, April 28, 2006

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The Lipoprotein Lipase Inhibitor ANGPTL3 Is Negatively Regulated by Thyroid Hormone^*

Charlotte Fugier, Jean-Jacques Tousaint, Xavier Prieur, Michelina Plateroti, Jacques Samarut, and Philippe Delerive¹

From the GlaxoSmithKline, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, 25 Avenue du Quebec, Les Ulis 91951, France and IFR 128, Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5161, INRA UMR 1237, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, Lyon 69364, France

Whereas the role of thyroid hormone is clearly established in the regulation of cholesterol homeostasis, its involvement in the control of serum triglyceride (TG) levels remains largely debated. Angiopoietin-like proteins 3 and 4 have recently been characterized as potent lipoprotein lipase inhibitors and therefore as important components of plasma triglyceride homeostasis. In the present study, the role of thyroid hormone in the regulation of both ANGPTL4 and ANGPTL3 gene expression was investigated. In vivo studies revealed that thyroid hormone down-regulates ANGPTL3 but not ANGPTL4 gene expression in hypothyroid rats. Using thyroid hormone receptor (TR)-deficient mice, we show that thyroid hormone regulates ANGPTL3 gene expression in a TR-dependent manner. Transfection studies revealed that this inhibition occurs at the transcriptional level in a DNA binding-independent fashion and requires the proximal (–171 to +66) region of the ANGPTL3 gene promoter. Moreover, site-directed mutagenesis experiments indicate that the HNF1 site within this proximal region mediates this TR-dependent repression. Finally, co-transfection studies and electrophoretic mobility shift assays suggest that TR antagonizes the HNF1 signaling pathway by inhibiting its transcriptional activity without interfering with its DNA-binding capacity. Taken together, our results lead to the identification of ANGPTL3 as a novel TR target gene and provide a new potential mechanism to explain the hypotriglyceridemic properties of TR agonists in vivo.

Received for publication, November 23, 2005 , and in revised form, January 27, 2006.

^* 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 correspondence should be addressed: GlaxoSmithKline R&D, CVU CEDD, 25 Ave. du Québec, 91951 Les Ulis, France. Tel.: 33-169296081; Fax: 33-169074892; E-mail: pxd14884{at}gsk.com.

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