Abstract
BackgroundMutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency.Methodology/Principal FindingsWe investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6), 129, and (B6-129) F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains.Conclusions/SignificanceOur results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease.
Highlights
ATP8B1, known as FIC1, is an ATP-dependent membrane transport protein in the Ptype ATPase family [1]
P-values reported in the text were derived from analysis of variance (ANOVA) comparing the groups mentioned; when sex differences were not apparent, data from males and females were sometimes combined for these latter tests
Atp8b1 mice were previously found to exhibit some of the characteristic phenotypic features of human ATP8B1 deficiency, such as elevation of bile salts, bilirubin and liver enzyme activities in serum, when fed a diet supplemented with 0.5% cholate
Summary
ATP8B1, known as FIC1 (familial intrahepatic cholestasis 1), is an ATP-dependent membrane transport protein in the Ptype ATPase family [1]. ATP8B1 belongs to the P4 subfamily of Ptype ATPases Members of this subfamily appear to function in phospholipid transport [2,3,4]; 14 P4 P-type ATPases are encoded in the human genome. Mutations in ATP8B1 result in cholestatic disease with an autosomal recessive mode of inheritance, and ranging in severity from mild and episodic (benign recurrent intrahepatic cholestasis, BRIC1) to chronic and progressive (progressive familial intrahepatic cholestasis; PFIC1) [1,8,9]. Mutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1deficient mouse serves as an animal model of human ATP8B1 deficiency
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