Liver fatty-acid-binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice

• Published in: Biochemical journal 2005-11, Vol.391 (Pt 3), p.549-560
• Main Authors: Martin, Gregory G, Atshaves, Barbara P, McIntosh, Avery L, Mackie, John T, Kier, Ann B, Schroeder, Friedhelm
• Format: Article
• Language: English
• Subjects: Animals; Bile Acids and Salts - blood; Bile Acids and Salts - metabolism; Cholesterol - metabolism; Cytoplasm - metabolism; Down-Regulation; Fatty Acid-Binding Proteins - deficiency; Fatty Acid-Binding Proteins - genetics; Fatty Acid-Binding Proteins - metabolism; Fatty Acids - metabolism; Gallbladder - metabolism; Gene Deletion; Gene Expression Regulation, Enzymologic; Lipid Metabolism; Liver - enzymology; Liver - metabolism; Male; Mice; Phenotype; Protein Binding; Up-Regulation
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/BJ20050296

Although the physiological roles of the individual bile acid synthetic enzymes have been extensively examined, relatively little is known regarding the function of intracellular bile acid-binding proteins. Male L-FABP (liver fatty-acid-binding protein) gene-ablated mice were used to determine a role for L-FABP, the major liver bile acid-binding protein, in bile acid and biliary cholesterol metabolism. First, in control-fed mice L-FABP gene ablation alone increased the total bile acid pool size by 1.5-fold, especially in gall-bladder and liver, but without altering the proportions of bile acid, cholesterol and phospholipid. Loss of liver L-FABP was more than compensated by up-regulation of: other liver cytosolic bile acid-binding proteins [GST (glutathione S-transferase), 3alpha-HSD (3alpha-hydroxysteroid dehydrogenase)], key hepatic bile acid synthetic enzymes [CYP7A1 (cholesterol 7alpha-hydroxylase) and CYP27A1 (sterol 27alpha-hydroxylase)], membrane bile acid translocases [canalicular BSEP (bile salt export pump), canalicular MRP2 (multidrug resistance associated protein 2), and basolateral/serosal OATP-1 (organic anion transporting polypeptide 1)], and positive alterations in nuclear receptors [more LXRalpha (liver X receptor alpha) and less SHP (short heterodimer partner)]. Secondly, L-FABP gene ablation reversed the cholesterol-responsiveness of bile acid metabolic parameters such that total bile acid pool size, especially in gall-bladder and liver, was reduced 4-fold, while the mass of biliary cholesterol increased 1.9-fold. The dramatically reduced bile acid levels in cholesterol-fed male L-FABP (-/-) mice were associated with reduced expression of: (i) liver cytosolic bile acid-binding proteins (L-FABP, GST and 3alpha-HSD), (ii) hepatic bile acid synthetic enzymes [CYP7A1, CYP27A1 and SCP-x (sterol carrier protein-x/3-ketoacyl-CoA thiolase)] concomitant with decreased positive nuclear receptor alterations (i.e. less LXRalpha and more SHP), and (iii) membrane bile acid transporters (BSEP, MRP2 and OATP-1). These are the first results suggesting a physiological role for the major cytosolic bile acid-binding protein (L-FABP) in influencing liver bile metabolic phenotype and gall-bladder bile lipids of male mice, especially in response to dietary cholesterol.