Decreased liver fatty acid binding capacity and altered liver lipid distribution in mice lacking the liver fatty acid-binding protein gene.
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 approximately 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.
Martin
Gregory G
GG
Department of Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, Raymond Stotzer Parkway, College Station, TX 77843-4467, USA.
Danneberg
Heike
H
Kumar
Leena S
LS
Atshaves
Barbara P
BP
Erol
Erdal
E
Bader
Michael
M
Schroeder
Friedhelm
F
Binas
Bert
B
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D002850:Chromatography, Gel; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism; D014280:Triglycerides / Q000737:chemistry / Q000378:metabolism
D002352:Carrier Proteins; D002788:Cholesterol Esters; D018076:DNA, Complementary; C493320:Fabp1 protein, mouse; C493321:Fabp1 protein, rat; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D011994:Recombinant Proteins; D014280:Triglycerides; C072087:sterol carrier proteins; D002784:Cholesterol; D000101:Acetyl-CoA C-Acetyltransferase; D005982:Glutathione Transferase; C013641:parinaric acid