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

Martin, Gregory G., Atshaves, Barbara P., McIntosh, Avery L., Mackie, John T., Kier, Ann B. and Schroeder, Friedhelm (2005) Liver fatty-acid-binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice. Biochemical Journal, 39 3: 549-560. doi:10.1042/BJ20050296


Author Martin, Gregory G.
Atshaves, Barbara P.
McIntosh, Avery L.
Mackie, John T.
Kier, Ann B.
Schroeder, Friedhelm
Title Liver fatty-acid-binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice
Journal name Biochemical Journal   Check publisher's open access policy
ISSN 0006-2936
0264-6021
Publication date 2005-11-01
Sub-type Article (original research)
DOI 10.1042/BJ20050296
Volume 39
Issue 3
Start page 549
End page 560
Total pages 2
Place of publication London, United Kingdom
Publisher Portland Press
Language eng
Subject 070709 Veterinary Pathology
Abstract 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), 3α-HSD (3α-hydroxysteroid dehydrogenase)], key hepatic bile acid synthetic enzymes [CYP7A1 (cholesterol 7α-hydroxylase) and CYP27A1 (sterol 27α-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 LXRα (liver X receptor a) 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 3α-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 LXRα 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.
Keyword Biochemistry
Bile acid
Cholesterol
Cholesteryl ester
Fatty-acid-binding protein
Gene ablation
Liver
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Veterinary Science Publications
 
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Created: Tue, 31 Mar 2009, 10:41:08 EST by Ms Karen Naughton on behalf of School of Veterinary Science