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J. Biol. Chem., Vol. 278, Issue 51, 51664-51672, December 19, 2003
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Decreased Hepatic Triglyceride Accumulation and Altered Fatty Acid Uptake in Mice with Deletion of the Liver Fatty Acid-binding Protein Gene*
¶
From the
Departments of Internal Medicine and Pharmacology and Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110
Liver fatty acid-binding protein (L-Fabp) is an abundant cytosolic lipid-binding protein with broad substrate specificity, expressed in mammalian enterocytes and hepatocytes. We have generated mice with a targeted deletion of the endogenous L-Fabp gene and have characterized their response to alterations in hepatic fatty acid flux following prolonged fasting. Chow-fed L-Fabp–/– mice were indistinguishable from wild-type littermates with regard to growth, serum and tissue lipid profiles, and fatty acid distribution within hepatic complex lipid species. In response to 48-h fasting, however, wild-type mice demonstrated a 
10-fold increase in hepatic triglyceride content while L-Fabp–/– mice demonstrated only a 2-fold increase. Hepatic VLDL secretion was decreased in L-Fabp–/– mice suggesting that the decreased accumulation of hepatic triglyceride was not the result of increased secretion. Fatty acid oxidation, as inferred from serum 
-hydroxybutyrate levels, was increased in response to fasting, although the increase in L-Fabp–/– mice was significantly reduced in comparison to wild-type controls, despite comparable induction of PPAR
target genes. Studies in primary hepatocytes revealed indistinguishable initial rates of oleate uptake, but longer intervals revealed reduced rates of uptake in fasted L-Fabp–/– mice. Oleate incorporation into cellular triglyceride and diacylglycerol was reduced in L-Fabp–/– mice although incorporation into phospholipid and cholesterol ester was no different than wild-type controls. These data point to an inducible defect in fatty acid utilization in fasted L-Fabp–/– mice that involves targeting of substrate for use in triglyceride metabolism.
Received for publication, August 25, 2003 , and in revised form, October 7, 2003.
* These studies were supported by Grants HL-38180, DK-56260, and DDRC grant DK-P30-52574 (to N. O. D.), a pilot and feasibility grant (to E. P. N.) by CNRU Grant DK-P30-56341, and PO1 HL-57278 (to R. W. G. and X. H.). 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.: 314-362-2027; Fax: 314-362-8959; E-mail: nod{at}im.wustl.edu.
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