Decreased Liver Fatty Acid Binding Capacity and Altered Liver Lipid Distribution in Mice Lacking the Liver Fatty Acid-binding Protein Gene

• Published in: The Journal of biological chemistry Vol. 278; no. 24; pp. 21429 - 21438
• Main Authors: Martin, Gregory G., Danneberg, Heike, Kumar, Leena S., Atshaves, Barbara P., Erol, Erdal, Bader, Michael, Schroeder, Friedhelm, Binas, Bert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.06.2003; American Society for Biochemistry and Molecular Biology
• Subjects: Acetyl-CoA C-Acetyltransferase - metabolism; Animals; Blotting, Western; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - physiology; Cell Membrane - metabolism; Cholesterol - metabolism; Cholesterol Esters - metabolism; Chromatography, Gel; Cytosol - metabolism; DNA, Complementary - metabolism; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Fatty Acids - metabolism; Fatty Acids, Unsaturated - metabolism; Glutathione Transferase - metabolism; Kinetics; Ligands; Lipid Metabolism; Liver - metabolism; Mice; Mice, Transgenic; Models, Genetic; Mutation; Neoplasm Proteins; Nerve Tissue Proteins; Phospholipids - metabolism; Protein Binding; Rats; Recombinant Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Subcellular Fractions - metabolism; Triglycerides - chemistry; Triglycerides - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M300287200

Although liver fatty acid-binding protein (L-FABP) is an important binding site for various hydrophobic ligands in hepatocytes, its in vivo significance is not understood. We have therefore created L-FABP null mice and report here their initial analysis, focusing on the impact of this mutation on hepatic fatty acid binding capacity, lipid composition, and expression of other lipid-binding proteins. Gel-filtered cytosol from L-FABP null liver lacked the main fatty acid binding peak in the fraction that normally comprises both L-FABP and sterol carrier protein-2 (SCP-2). The binding capacity for cis-parinaric acid was decreased >80% in this region. Molar ratios of cholesterol/cholesterol ester, cholesteryl ester/triglyceride, and cholesterol/phospholipid were 2- to 3-fold greater, reflecting up to 3-fold absolute increases in specific lipid classes in the order cholesterol > cholesterol esters > phospholipids. In contrast, the liver pool sizes of nonesterified fatty acids and triglycerides were not altered. However, hepatic deposition of a bolus of intravenously injected [14C]oleate was markedly reduced, showing altered lipid pool turnover. An increase of ∼75% of soluble SCP-2 but little or no change of other soluble (glutathione S-transferase, albumin) and membrane (fatty acid transport protein, CD36, aspartate aminotransferase, caveolin) fatty acid transporters was measured. These results (i) provide for the first time a quantitative assessment of the contribution of L-FABP to cytosolic fatty acid binding capacity, (ii) establish L-FABP as an important determinant of hepatic lipid composition and turnover, and (iii) suggest that SCP-2 contributes to the accumulation of cholesterol in L-FABP null liver.