74 THE GALLBLADDER DYSFUNCTIONS AND CONTRIBUTES TO IMPAIRED BILE SALT HOMEOSTASIS IN CYSTIC FIBROSIS

The molecular pathogenesis of cystic fibrosis (CF) liver disease is unknown. This study investigates its earliest pathophysiological manifestations employing a mouse model carrying ΔF508, the commonest human CF mutation. We hypothesized that, if increased bile salt spillage into the colon occurs as in the human disease, then this should lead to a hydrophobic bile salt profile and to “hyperbilirubinbilia” because of induced enterohepatic cycling of unconjugated bilirubin. Hyperbilirubinbilia may then lead to an increased bile salt-to-phospholipid ratio in bile and, following hydrolysis, precipitation of divalent metal salts of unconjugated bilirubin. We document in CF mice elevated fecal bile acid excretion and biliary secretion of more hydrophobic bile salts compared with control wild-type mice. Biliary secretion rates of bilirubin monoglucuronosides, bile salts, phospholipids, and cholesterol are increased significantly with an augmented bile salt-to-phospholipid ratio. Quantitative histopathology of CF livers displays mild early cholangiopathy in ≈53% of mice and multifocal divalent metal salt deposition in cholangiocytes. We conclude that increased fecal bile acid loss leads to more hydrophobic bile salts in hepatic bile and to hyperbilirubinbilia, a major contributor in augmenting the bile salt-to-phospholipid ratio and endogenous β-glucuronidase hydrolysis of bilirubin glucuronosides. The confluence of these perturbations damages intrahepatic bile ducts and facilitates entrance of unconjugated bilirubin into cholangiocytes. This study of the earliest stages of CF liver disease provides a framework for investigating the molecular pathophysiology of more advanced disease in murine models and in humans with CF.

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Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00258.2011 ◽

2012 ◽

Vol 302 (9) ◽

pp. G1035-G1042 ◽

Cited By ~ 9

Author(s):

Frank A. J. A. Bodewes ◽

Marjan Wouthuyzen-Bakker ◽

Marcel J. Bijvelds ◽

Rick Havinga ◽

Hugo R. de Jonge ◽

...

Keyword(s):

Cystic Fibrosis ◽

Liver Disease ◽

Bile Salt ◽

Bile Flow ◽

Cystic Fibrosis Transmembrane Regulator ◽

Pool Size ◽

Therapeutic Action ◽

Wild Type ◽

Bile Composition ◽

Cystic Fibrosis Transmembrane

Cystic fibrosis liver disease (CFLD) is treated with ursodeoxycholate (UDCA). Our aim was to evaluate, in cystic fibrosis transmembrane regulator knockout ( Cftr −/−) mice and wild-type controls, whether the supposed therapeutic action of UDCA is mediated via choleretic activity or effects on bile salt metabolism. Cftr −/− mice and controls, under general anesthesia, were intravenously infused with tauroursodeoxycholate (TUDCA) in increasing dosage or were fed either standard or UDCA-enriched chow (0.5% wt/wt) for 3 wk. Bile flow and bile composition were characterized. In chow-fed mice, we analyzed bile salt synthesis and pool size of cholate (CA). In both Cftr −/− and controls intravenous TUDCA stimulated bile flow by ∼250% and dietary UDCA by ∼500%, compared with untreated animals ( P < 0.05). In non-UDCA-treated Cftr −/− mice, the proportion of CA in bile was higher compared with that in controls (61 ± 4 vs. 46 ± 4%; P < 0.05), accompanied by an increased CA synthesis [16 ± 1 vs. 10 ± 2 μmol·h−1·100 g body wt (BW)−1; P < 0.05] and CA pool size (28 ± 3 vs. 19 ± 1 μmol/100 g BW; P < 0.05). In both Cftr −/− and controls, UDCA treatment drastically reduced the proportion of CA in bile below 5% and diminished CA synthesis (2.3 ± 0.3 vs. 2.2 ± 0.4 μmol·day−1·100 g BW−1; nonsignificant) and CA pool size (3.6 ± 0.6 vs. 1.5 ± 0.3 μmol/100 g BW; P < 0.05). Acute TUDCA infusion and chronic UDCA treatment both stimulate bile flow in cystic fibrosis conditions independently from Cftr function. Chronic UDCA treatment reduces the hydrophobicity of the bile salt pool in Cftr −/− mice. These results support a potential beneficial effect of UDCA on bile flow and bile salt metabolism in cystic fibrosis conditions.

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Liver resection results in altered bile salt homeostasis

HPB ◽

10.1016/j.hpb.2016.02.387 ◽

2016 ◽

Vol 18 ◽

pp. e163

Author(s):

K.V.K. Koelfat ◽

F.G. Schaap ◽

J.G. Bloemen ◽

A.K. Groen ◽

P.L.M. Jansen ◽

...

Keyword(s):

Liver Resection ◽

Bile Salt ◽

Salt Homeostasis

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Na+-taurocholate cotransporting polypeptide (NTCP/SLC10A1) ortholog in the marine skate Leucoraja erinacea is not a physiological bile salt transporter

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00302.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. R477-R484 ◽

Cited By ~ 1

Author(s):

Dongke Yu ◽

Han Zhang ◽

Daniel A. Lionarons ◽

James L. Boyer ◽

Shi-Ying Cai

Keyword(s):

Bile Salt ◽

Dehydroepiandrosterone Sulfate ◽

Salt Transport ◽

Uptake System ◽

Physiological Concentration ◽

Uptake Assay ◽

Solute Carrier ◽

The Brain ◽

Salt Homeostasis ◽

Bile Salt Transport

The Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1) is a hepatocyte-specific solute carrier, which plays an important role in maintaining bile salt homeostasis in mammals. The absence of a hepatic Na+-dependent bile salt transport system in marine skate and rainbow trout raises a question regarding the function of the Slc10a1 gene in these species. Here, we have characterized the Slc10a1 gene in the marine skate, Leucoraja erinacea. The transcript of skate Slc10a1 (skSlc10a1) encodes 319 amino acids and shares 46% identity to human NTCP (hNTCP) with similar topology to mammalian NTCP. SkSlc10a1 mRNA was mostly confined to the brain and testes with minimal expression in the liver. An FXR-bile salt reporter assay indicated that skSlc10a1 transported taurocholic acid (TCA) and scymnol sulfate, but not as effectively as hNTCP. An [3H]TCA uptake assay revealed that skSlc10a1 functioned as a Na+-dependent transporter, but with low affinity for TCA ( Km = 92.4 µM) and scymnol sulfate ( Ki = 31 µM), compared with hNTCP (TCA, Km = 5.4 µM; Scymnol sulfate, Ki = 3.5 µM). In contrast, the bile salt concentration in skate plasma was 2 µM, similar to levels seen in mammals. Interestingly, skSlc10a1 demonstrated transport activity for the neurosteroids dehydroepiandrosterone sulfate and estrone-3-sulfate at physiological concentration, similar to hNTCP. Together, our findings indicate that skSlc10a1 is not a physiological bile salt transporter, providing a molecular explanation for the absence of a hepatic Na+-dependent bile salt uptake system in skate. We speculate that Slc10a1 is a neurosteroid transporter in skate that gained its substrate specificity for bile salts later in vertebrate evolution.

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