TY - JOUR
T1 - Increased susceptibility to diet-induced gallstones in liver fatty acid binding protein knockout mice
AU - Xie, Yan
AU - Newberry, Elizabeth P.
AU - Kennedy, Susan M.
AU - Luo, Jianyang
AU - Davidson, Nicholas O.
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
KW - Bile acid metabolism
KW - Cholesterol absorption
KW - Enterohepatic lipid flux
KW - Genetic susceptibility
KW - Hepatic steatosis
KW - Quantitative trait locus
UR - http://www.scopus.com/inward/record.url?scp=67649675014&partnerID=8YFLogxK
U2 - 10.1194/jlr.M800645-JLR200
DO - 10.1194/jlr.M800645-JLR200
M3 - Article
C2 - 19136665
AN - SCOPUS:67649675014
SN - 0022-2275
VL - 50
SP - 977
EP - 987
JO - Journal of lipid research
JF - Journal of lipid research
IS - 5
ER -