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Journal of Lipid Research, Vol. 50, 977-987, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Yan Xie, Elizabeth P. Newberry, Susan M. Kennedy, Jianyang Luo and Nicholas O. Davidson¹

Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two tables.

This work was supported in part by grants from the National Institutes of Health (R01 DK-056260 and R37 HL-038180) to N.O.D. and the Washington University Digestive Diseases Research Core Center (P30 DK052574) to N.O.D., in particular the Morphology and Functional Genomics Cores.

Published, JLR Papers in Press, January 9, 2009.

¹ To whom correspondence should be addressed. e-mail: nod{at}wustl.edu

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.

Supplementary key words genetic susceptibility • quantitative trait locus • bile acid metabolism • enterohepatic lipid flux • hepatic steatosis • cholesterol absorption

Abbreviations: BA, bile acid; ChMC, cholesterol monohydrate crystal; FPLC, fast-protein liquid chromatography; LD, lithogenic diet; L-Fabp, Liver fatty acid binding protein; qRT-PCR, quantitative RT-PCR; TG, triglyceride

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