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

Yan Xie,Elizabeth P Newberry,Susan M Kennedy,Jianyang Luo,Nicholas O Davidson

doi:10.1194/jlr.m800645-jlr200

Yan Xie, Elizabeth P Newberry + Show 3 more

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https://doi.org/10.1194/jlr.m800645-jlr200

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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.

Highlights

Quantitative trait mapping identified a locus colocalizing with Liver fatty acid binding protein (L-Fabp), encoding liver fatty acid binding protein, as a positional candidate for murine gallstone susceptibility
This pattern was augmented after 4 weeks of lithogenic diet (LD) feeding (Fig. 1B) and was associated with increased hepatic secretion of cholesterol-rich lipoproteins in L-Fabp2/2 mice (Fig. 1C), VLDL-TG secretion was comparable in L-Fabp2/2 and wild-type mice
Our findings revealed a significant decrease in ileal Asbt mRNA and protein expression in chow-fed L-Fabp2/2 mice and decreased mRNA abundance of the transcription factor Lrh-1. These findings demonstrate that ileal Asbt expression and enterohepatic bile acid (BA) metabolism are altered in chow-fed L-Fabp2/2 mice, a finding amplified below

Summary

Introduction

Quantitative trait mapping identified a locus colocalizing with L-Fabp, encoding liver fatty acid binding protein, as a positional candidate for murine gallstone susceptibility. The increase in biliary BA secretion and enterohepatic pool size in LD-fed L-Fabp2/2 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-Fabp2/2 mice.—Xie, Y., E. Increased susceptibility to diet-induced gallstones in liver fatty acid binding protein knockout mice. Our understanding of the genetic factors that predispose to gallstone formation has been advanced through study of inbred murine crosses in which susceptibility loci have been mapped using diet-induced gallstone formation as a quantitative trait Using this approach, .23 quantitative trait loci have been mapped, allowing formal evaluation of potential candidate genes [reviewed in [2]]. A role for L-Fabp was proposed in modifying the response to cholesterol feeding based on a striking gender-

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