Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene.
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 approximately 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 beta-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 alpha 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.
Newberry
Elizabeth P
EP
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Xie
Yan
Y
Kennedy
Susan
S
Han
Xianlin
X
Buhman
Kimberly K
KK
Luo
Jianyang
J
Gross
Richard W
RW
Davidson
Nicholas O
NO
D000222:Adaptation, Physiological; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D005215:Fasting; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism*; D017353:Gene Deletion; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D019301:Oleic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000378:metabolism*
D002352:Carrier Proteins; C493320:Fabp1 protein, mouse; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D008079:Lipoproteins, VLDL; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014280:Triglycerides; D019301:Oleic Acid