Increased susceptibility to diet-induced gallstones in liver fatty acid binding protein knockout mice.

Abstract

Quantitative trait mapping identified a locus colocalizing with L-Fabp, encoding liver fatty acid binding protein, as a positional candidate for murine gallstone susceptibility. When fed a lithogenic diet (LD) for 2 weeks, L-Fabp(-/-) mice became hypercholesterolemic with increased hepatic VLDL cholesterol secretion. Seventy-five percent of L-Fabp(-/-) mice developed solid gallstones compared with 6% of wild-type mice with an increased gallstone score (3.29 versus 0.62, respectively; P < 0.01). Hepatic free cholesterol content, biliary cholesterol secretion, and the cholesterol saturation index of hepatic bile were increased in LD-fed L-Fabp(-/-) mice. Chow-fed L-Fabp(-/-) mice demonstrated increased fecal bile acid (BA) excretion accompanied by decreased ileal Asbt expression. By contrast, there was an increased BA pool and decreased fecal BA excretion in LD-fed L-Fabp(-/-) mice, associated with increased proximal intestinal Asbt mRNA expression, suggesting that intestinal BA absorption was enhanced in LD-fed L-Fabp(-/-) mice. The increase in biliary BA secretion and enterohepatic pool size in LD-fed L-Fabp(-/-) mice was accompanied by downregulation of Cyp7a1 mRNA and increased intestinal mRNA abundance of Fgf-15, Fxr, and Fabp6. These findings suggest that changes in hepatic cholesterol metabolism and biliary lipid secretion as well as changes in enterohepatic BA metabolism increase gallstone susceptibility in LD fed L-Fabp(-/-) mice.

• Authors: Yan Xie, Elizabeth P Newberry, Susan M Kennedy, Jianyang Luo, Nicholas O Davidson
• Journal: Journal of lipid research (J Lipid Res) Vol. 50 Issue 5 Pg. 977-87 (May 2009) ISSN: 0022-2275 [Print] United States
• PMID: 19136665 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bile Acids and Salts
• Fatty Acid-Binding Proteins
• Cholesterol

Topics

• Animals
• Bile Acids and Salts (metabolism)
• Cholesterol (metabolism)
• Diet
• Disease Susceptibility
• Fatty Acid-Binding Proteins (genetics, metabolism)
• Feces (chemistry)
• Gallbladder (pathology)
• Gallstones (chemistry, metabolism, pathology)
• Gene Expression Profiling
• Liver (chemistry)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Sequence Data
• Quantitative Trait Loci
• Signal Transduction (physiology)