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Papers In Press, published online ahead of print November 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600303-JLR200

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Journal of Lipid Research, Vol. 47, 2503-2514, November 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Apolipoprotein A-IV is regulated by nutritional and metabolic stress: involvement of glucocorticoids, HNF-4, and PGC-1

Elyhisha A. Hanniman^*, Gilles Lambert, Yusuke Inoue, Frank J. Gonzalez and Christopher J. Sinal^1,*

^* Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
University of Nantes Medical School, Institut National de la Santé et de la Recherche Médicale U539, Centre Hospitalier Universitaire de Nantes Hôtel Dieu, Nantes, France
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD

The online version of this article (available at http://www.jlr.org) contains additional two tables.

Published, JLR Papers in Press, August 23, 2006.

¹ To whom correspondence should be addressed. e-mail: csinal{at}dal.ca

Apolipoprotein A-IV (apoA-IV) is a 46 kDa glycoprotein that associates with triglyceride-rich and high density lipoproteins. Blood levels of apoA-IV generally correlate with triglyceride levels and are increased in diabetic patients. This study investigated the mechanisms regulating the in vivo expression of apoA-IV in the liver and intestine of mice in response to changes in nutritional status. Fasting markedly increased liver and ileal apoA-IV mRNA and plasma protein concentrations. This induction was associated with increased serum glucocorticoid levels and was abolished by adrenalectomy. Treatment with dexamethasone increased apoA-IV expression in adrenalectomized mice. Marked increases of apoA-IV expression were also observed in two murine models of diabetes. Reporter gene analysis of the murine and human apoA-IV/C-III promoters revealed a conserved cooperative activation by the hepatic nuclear factor-4 (HNF-4) and the peroxisome proliferator-activated receptor coactivator-1 (PGC-1) but no evidence of a direct regulatory role for the glucocorticoid receptor. Consistent with these in vitro data, induction of apoA-IV in response to fasting was accompanied by increases in HNF-4 and PGC-1 expression and was abolished in liver-specific HNF-4-deficient mice. Together, these results indicate that the induction of apoA-IV expression in fasting and diabetes likely involves PGC-1-mediated coactivation of HNF-4 in addition to glucocorticoid-dependent actions.

Supplementary key words glucocorticoid receptor • fasting • diabetes • adrenalectomy • hepatic nuclear factor-4 • peroxisome proliferator-activated receptor coactivator-1

Abbreviations: apoA-IV, apolipoprotein A-IV; Cyp, cytochrome P450; GR, glucocorticoid receptor; HNF, hepatic nuclear factor; HRE, hormone response element; PGC-1, peroxisome proliferator-activated receptor coactivator-1; PPAR, peroxisome proliferator-activated receptor; QPCR, real-time quantitative polymerase chain reaction; TBS-T, Tris-buffered saline plus Tween-20

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