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 [ (14)C] oleate was markedly reduced, showing altered lipid pool turnover. An increase of similar to 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.