Increased susceptibility to diet-induced gallstones in liver fatty acid binding protein knockout mice.
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.
Xie
Yan
Y
Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, St Louis, MO 63110, USA.
Newberry
Elizabeth P
EP
Kennedy
Susan M
SM
Luo
Jianyang
J
Davidson
Nicholas O
NO
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004032:Diet; D004198:Disease Susceptibility; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005704:Gallbladder / Q000473:pathology; D042882:Gallstones / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D040641:Quantitative Trait Loci; D015398:Signal Transduction / Q000502:physiology
D001647:Bile Acids and Salts; D050556:Fatty Acid-Binding Proteins; D002784:Cholesterol