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J. Biol. Chem., Vol. 278, Issue 49, 49512-49516, December 5, 2003
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Targeted Deletion of Fatty Acid Transport Protein-4 Results in Early Embryonic Lethality*
From the
¶Palo Alto Medical Foundation and Stanford University School of Medicine, Palo Alto, California 94301, The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139
Fatty acid transport protein-4 (FATP4) is the major FATP in the small intestine. We previously demonstrated, using in vitro antisense experiments, that FATP4 is required for fatty acid uptake into intestinal epithelial cells. To further examine the physiological role of FATP4, mice carrying a targeted deletion of FATP4 were generated. Deletion of one allele of FATP4 resulted in 48% reduction of FATP4 protein levels and a 40% reduction of fatty acid uptake by isolated enterocytes. However, loss of one FATP4 allele did not cause any detectable effects on fat absorption on either a normal or a high fat diet. Deletion of both FATP4 alleles resulted in embryonic lethality as crosses between heterozygous FATP4 parents resulted in no homozygous offspring; furthermore, no homozygous embryos were detected as early as day 9.5 of gestation. Early embryonic lethality has been observed with deletion of other genes involved in lipid absorption in the small intestine, namely microsomal triglyceride transfer protein and apolipoprotein B, and has been attributed to a requirement for fat absorption early in embryonic development across the visceral endoderm. In mice, the extraembryonic endoderm supplies nutrients to the embryo prior to development of a chorioallantoic placenta. In wild-type mice we found that FATP4 protein is highly expressed by the epithelial cells of the visceral endoderm and localized to the brush-border membrane of extraembryonic endodermal cells. This localization is consistent with a role for FATP4 in fat absorption in early embryogenesis and suggests a novel requirement for FATP4 function during development.
Received for publication, September 3, 2003 , and in revised form, September 24, 2003.
* This work was supported in part by American Heart Association beginning Grant-in-aid 0265311Y and a Stanford Digestive Disease Center Pilot grant (to A. S.). 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. Tel.: 650-614-3293; Fax: 650-329-9114; E-mail: AStahl{at}Stanford.edu.
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