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Journal of Lipid Research, Vol. 49, 961-972, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Intestinal fatty acid binding protein regulates mitochondrion β-oxidation and cholesterol uptake

Alain Montoudis^*, Ernest Seidman^,, François Boudreau, Jean-François Beaulieu, Daniel Menard, Mounib Elchebly^**, Geneviève Mailhot^*, Alain-Theophile Sane^*, Marie Lambert, Edgard Delvin^** and Emile Levy^1,*,

^* Department of Nutrition, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada
^** Department of Biochemistry, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada
Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada
Research Institute, McGill University, Campus Montreal General Hospital, Montreal, Quebec, Canada
Group on the Intestinal Epithelium, Canadian Institute of Health Research, and Department of Cellular Biology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada

Published, JLR Papers in Press, January 30, 2008.

¹ To whom correspondence should be addressed. e-mail: emile.levy{at}recherche-ste-justine.qc.ca

The role of intestinal fatty acid binding protein (I-FABP) in lipid metabolism remains elusive. To address this issue, normal human intestinal epithelial cells (HIEC-6) were transfected with cDNA to overexpress I-FABP and compared with cells treated with empty pQCXIP vector. I-FABP overexpression stimulated mitochondrial [U-¹⁴C]oleate oxidation to CO₂ and acid-soluble metabolites via mechanisms including the upregulation of protein expression and the activity of carnitine palmitoyltransferase 1, a critical enzyme controlling the entry of fatty acid (FA) into mitochondria, and increased activity of 3-hydroxyacyl-CoA dehydrogenase, a mitochondrial β-oxidation enzyme. On the other hand, the gene and protein expression of the key enzymes FA synthase and acetyl-coenzyme A carboxylase 2 was decreased, suggesting diminished lipogenesis. Furthermore, I-FABP overexpression caused a decline in [¹⁴C]free cholesterol (CHOL) incorporation. Accordingly, a significant lessening was observed in the gene expression of Niemann Pick C1-Like 1, a mediator of CHOL uptake, along with an increase in the transcripts and protein content of ABCA1 and ABCG5/ABCG8, acting as CHOL efflux pumps. Furthermore, I-FABP overexpression resulted in increased levels of mRNA, protein mass, and activity of HMG-CoA reductase, the rate-limiting step in CHOL synthesis. Scrutiny of the nuclear receptors revealed augmented peroxisome proliferator-activated receptor , and reduced liver X receptor- in HIEC-6 overexpressing I-FABP. Finally, I-FABP overexpression did not influence acyl-coenzyme A oxidase 1, which catalyzes the first rate-limiting step in peroxisomal FA β-oxidation. Overall, our data suggest that I-FABP may influence mitochondrial FA oxidation and CHOL transport by regulating gene expression and interaction with nuclear receptors.

Supplementary key words I-FABP • HIEC-6 • cholesterol metabolism

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