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Cholic acid induces a Cftr dependent biliary secretion and liver growth response in mice.

Bodewes FA, Bijvelds MJ, de Vries W, Baller JF, Gouw AS, de Jonge HR, Verkade HJ - PLoS ONE (2015)

Bottom Line: The cause of Cystic fibrosis liver disease (CFLD), is unknown.For this reason, we hypothesize that, CFTR dependent variations, in the hepatic handling of hydrophobic bile salts, are related to the development CFLD.Chronic cholate administration induces a cystic fibrosis-specific hepatobiliary phenotype, including changes in bile composition.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Groningen, Beatrix Children's Hospital-University Medical Center, Groningen, The Netherlands.

ABSTRACT
The cause of Cystic fibrosis liver disease (CFLD), is unknown. It is well recognized that hepatic exposure to hydrophobic bile salts is associated with the development of liver disease. For this reason, we hypothesize that, CFTR dependent variations, in the hepatic handling of hydrophobic bile salts, are related to the development CFLD. To test our hypothesis we studied, in Cftr-/- and control mice, bile production, bile composition and liver pathology, in normal feeding condition and during cholate exposure, either acute (intravenous) or chronic (three weeks via the diet). In Cftr-/- and control mice the basal bile production was comparable. Intravenous taurocholate increased bile production to the same extent in Cftr-/- and control mice. However, chronic cholate exposure increased the bile flow significantly less in Cftr-/- mice than in controls, together with significantly higher biliary bile salt concentration in Cftr-/- mice. Prolonged cholate exposure, however, did not induce CFLD like pathology in Cftr-/- mice. Chronic cholate exposure did induce a significant increase in liver mass in controls that was absent in Cftr-/- mice. Chronic cholate administration induces a cystic fibrosis-specific hepatobiliary phenotype, including changes in bile composition. These changes could not be associated with CFLD like pathological changes in CF mouse livers. However, chronic cholate administration induces liver growth in controls that is absent in Cftr-/- mice. Our findings point to an impaired adaptive homeotrophic liver response to prolonged hydrophobic bile salt exposure in CF conditions.

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Hepatic Cyp7a1 mRNA expression Cftr knockout mice (Cftr-/-) and controls, fed a control diet or a cholic acid (CA) containing diet for 3 weeks.Hepatic Cyp7a1 mRNA expression after a control (A) or 0.5%-CA (wt/wt) chow diet (B) for three weeks. Cyp7a1 mRNA levels were normalized to a housekeeping gene (β-actin) in Cftr knockout mice (Cftr-/-) and control littermates (Cftr+/+). Data are presented as means ± SEM of N = 5–7 mice per group. *P-value<0.05.
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pone.0117599.g003: Hepatic Cyp7a1 mRNA expression Cftr knockout mice (Cftr-/-) and controls, fed a control diet or a cholic acid (CA) containing diet for 3 weeks.Hepatic Cyp7a1 mRNA expression after a control (A) or 0.5%-CA (wt/wt) chow diet (B) for three weeks. Cyp7a1 mRNA levels were normalized to a housekeeping gene (β-actin) in Cftr knockout mice (Cftr-/-) and control littermates (Cftr+/+). Data are presented as means ± SEM of N = 5–7 mice per group. *P-value<0.05.

Mentions: Hydrophobic bile salts are regarded as strong ligands for the nuclear receptor Fxr, which is, among other functions, also involved in bile acid synthesis regulation. The observed significant difference in DCA proportion upon CA treatment could correspond with differences in bile synthesis rates between the genotypes. To address this possibility, we determined the mRNA expression of hepatic Cyp7a1, encoding the rate-limiting enzyme in bile salt synthesis from cholesterol. During normal diet, the hepatic expression of Cyp7a1 was similar in Cftr-/- and control mice. After prolonged CA exposure, however, the Cyp7a1 expression was completely suppressed in control mice, but unaffected in Cftr-/- mice (Fig. 3A and B).


Cholic acid induces a Cftr dependent biliary secretion and liver growth response in mice.

Bodewes FA, Bijvelds MJ, de Vries W, Baller JF, Gouw AS, de Jonge HR, Verkade HJ - PLoS ONE (2015)

Hepatic Cyp7a1 mRNA expression Cftr knockout mice (Cftr-/-) and controls, fed a control diet or a cholic acid (CA) containing diet for 3 weeks.Hepatic Cyp7a1 mRNA expression after a control (A) or 0.5%-CA (wt/wt) chow diet (B) for three weeks. Cyp7a1 mRNA levels were normalized to a housekeeping gene (β-actin) in Cftr knockout mice (Cftr-/-) and control littermates (Cftr+/+). Data are presented as means ± SEM of N = 5–7 mice per group. *P-value<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4334531&req=5

pone.0117599.g003: Hepatic Cyp7a1 mRNA expression Cftr knockout mice (Cftr-/-) and controls, fed a control diet or a cholic acid (CA) containing diet for 3 weeks.Hepatic Cyp7a1 mRNA expression after a control (A) or 0.5%-CA (wt/wt) chow diet (B) for three weeks. Cyp7a1 mRNA levels were normalized to a housekeeping gene (β-actin) in Cftr knockout mice (Cftr-/-) and control littermates (Cftr+/+). Data are presented as means ± SEM of N = 5–7 mice per group. *P-value<0.05.
Mentions: Hydrophobic bile salts are regarded as strong ligands for the nuclear receptor Fxr, which is, among other functions, also involved in bile acid synthesis regulation. The observed significant difference in DCA proportion upon CA treatment could correspond with differences in bile synthesis rates between the genotypes. To address this possibility, we determined the mRNA expression of hepatic Cyp7a1, encoding the rate-limiting enzyme in bile salt synthesis from cholesterol. During normal diet, the hepatic expression of Cyp7a1 was similar in Cftr-/- and control mice. After prolonged CA exposure, however, the Cyp7a1 expression was completely suppressed in control mice, but unaffected in Cftr-/- mice (Fig. 3A and B).

Bottom Line: The cause of Cystic fibrosis liver disease (CFLD), is unknown.For this reason, we hypothesize that, CFTR dependent variations, in the hepatic handling of hydrophobic bile salts, are related to the development CFLD.Chronic cholate administration induces a cystic fibrosis-specific hepatobiliary phenotype, including changes in bile composition.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Groningen, Beatrix Children's Hospital-University Medical Center, Groningen, The Netherlands.

ABSTRACT
The cause of Cystic fibrosis liver disease (CFLD), is unknown. It is well recognized that hepatic exposure to hydrophobic bile salts is associated with the development of liver disease. For this reason, we hypothesize that, CFTR dependent variations, in the hepatic handling of hydrophobic bile salts, are related to the development CFLD. To test our hypothesis we studied, in Cftr-/- and control mice, bile production, bile composition and liver pathology, in normal feeding condition and during cholate exposure, either acute (intravenous) or chronic (three weeks via the diet). In Cftr-/- and control mice the basal bile production was comparable. Intravenous taurocholate increased bile production to the same extent in Cftr-/- and control mice. However, chronic cholate exposure increased the bile flow significantly less in Cftr-/- mice than in controls, together with significantly higher biliary bile salt concentration in Cftr-/- mice. Prolonged cholate exposure, however, did not induce CFLD like pathology in Cftr-/- mice. Chronic cholate exposure did induce a significant increase in liver mass in controls that was absent in Cftr-/- mice. Chronic cholate administration induces a cystic fibrosis-specific hepatobiliary phenotype, including changes in bile composition. These changes could not be associated with CFLD like pathological changes in CF mouse livers. However, chronic cholate administration induces liver growth in controls that is absent in Cftr-/- mice. Our findings point to an impaired adaptive homeotrophic liver response to prolonged hydrophobic bile salt exposure in CF conditions.

Show MeSH
Related in: MedlinePlus