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J. Biol. Chem., Vol. 279, Issue 20, 21206-21216, May 14, 2004

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The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element^*

Jean-François Paré, Daniel Malenfant, Chantal Courtemanche, Mariève Jacob-Wagner, Sylvie Roy, Denis Allard, and Luc Bélanger

From the Département de biologie médicale, Faculté de médecine, Le Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Québec G1R 2J6, Canada

The fetoprotein transcription factor (FTF) gene was inactivated in the mouse, with a lacZ gene inserted inframe into exon 4. LacZ staining of FTF+/- embryos shows that the mFTF gene is activated at initial stages of zygotic transcription. FTF gene activity is ubiquitous at the morula and blastocyst stages and then follows expression patterns indicative of multiple FTF functions in fetal development. FTF-/- embryos die at E6.5–7.5, with features typical of visceral endoderm dysfunction. Adult FTF+/- mice are hypocholesterolemic, and express liver FTF at about 40% of the normal level. Overexpression of liver FTF in transgenic mice indicates in vivo that FTF is an activator of CYP7A1. However, CYP7A1 expression is increased in FTF+/- liver. Gene expression profiles indicate that higher CYP7A1 expression is caused by attenuated liver cell stress signaling. Diet experiments support a model where FTF is quenched both by activated c-Jun, and by SHP as a stronger feedback mechanism to repress CYP7A1. A DR4 element is conserved in the FTF gene promoter and activated by LXR-RXR and TR-RXR, qualifying the FTF gene as a direct metabolic sensor. Liver FTF increases in rats treated with thyroid hormone or a high cholesterol diet. The FTF DR4 element tightens functional links between FTF and LXR in cholesterol homeostasis and can explain transient surges of FTF gene activities during development and FTF levels lower than predicted in FTF+/- liver. The FTF-lacZ mouse establishes a central role for FTF in developmental, nutritive, and metabolic functions from early embryogenesis through adulthood.

Received for publication, February 11, 2004 , and in revised form, March 8, 2004.

^* This work was supported by Grant MT-6478 from the Canadian Institutes of Health Research. 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.

Recipient of a doctoral studentship from Fonds de la Recherche en Santé du Québec and Fonds pour la Formation de Chercheurs et l'Aide à la Recherche.

To whom correspondence should be addressed: Cancer Research Centre, L'Hôtel-Dieu de Québec, Québec G1R 2J6, Canada. Tel.: 418-525-4444 (ext. 15543); Fax: 418-691-5489; E-mail: luc.belanger{at}crhdq.ulaval.ca.

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