Lithocholic acid downregulates vitamin D effects in human osteoblasts

Ruiz-Gaspà, Sílvia; Guañabens, Núria; Enjuanes, Anna; Peris, Pilar; Martínez-Ferrer, À.; Osaba, Marı́a J. Martı́nez de; González, Baldomero; Álvarez, Luisa; Monegal, Ana; Combalía, Andrés; Parés, Albert

doi:10.1111/j.1365-2362.2009.02230.x

Cited by 61 publications

(46 citation statements)

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“…Vitamin D levels are regulated through degradation via 24-hydroxylase, and vitamin D induces the expression of this enzyme, thus controlling its own catabolism [33, 34]. Of note, bile acids such as lithocholic acid have been shown to decrease this stimulatory effect of vitamin D and influence a broad spectrum of signaling pathways via the nuclear receptors VDR, FXR and PXR [35–38]. In fact, minor changes in bile salt composition have been shown to affect hepatic fibrogenesis in ABCB4-deficient mice [39], although the expression of the genes encoding the rate-limiting enzymes for bile salt synthesis ( Cyp7a1 ) and conversion to the hydrophobic cholic acid ( Cyp8b1 ) showed no major differences across the groups.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D modulates biliary fibrosis in ABCB4-deficient mice

et al. 2014

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PurposeImpaired vitamin D receptor signaling represents an aggravating factor during liver injury, and recent studies suggest that vitamin D might exert a protective role in chronic hepatobiliary diseases. We hypothesized that vitamin D supplementation would ameliorate liver fibrosis in ATP-binding cassette transporter B4 knockout (Abcb4−/−) mice as a preclinical model of sclerosing cholangitis.MethodsAbcb4−/− and wild-type mice were fed a regular chow diet (600 IU vitamin D/kg food) or diets with lower (100 IU/kg) and higher (2,400 IU/kg) vitamin D concentrations for 12 weeks. Serum 25-hydroxyvitamin D concentrations were measured by chemiluminescence immunoassays. Liver injury and biliary fibrosis were assessed by liver enzyme activities, histopathology and hepatic collagen contents. Hepatic mRNA expression of markers for fibrosis, vitamin D and bile acid metabolism were analyzed by quantitative PCR.ResultsDifferent vitamin D concentrations were observed depending on genotype and diet group, with Abcb4−/− mice on the control diet showing lower vitamin D concentrations compared to wild-type mice. Abcb4−/− animals on the low vitamin D diet demonstrated the most advanced liver fibrosis and highest hepatic collagen contents. Feeding Abcb4−/− mice a high vitamin D diet enriched serum vitamin D levels, lowered liver enzyme activities, altered expression levels of profibrogenic genes and ameliorated, in part, liver injury.ConclusionsThis is the first report to demonstrate that fibrogenesis in the established Abcb4−/− model is influenced by vitamin D supplementation. Since vitamin D modulates sclerosing cholangitis in vivo, we speculate that sufficient vitamin D intake might improve liver damage and induce antifibrotic effects in chronic cholestasis in humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s12072-014-9548-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Vitamin D modulates biliary fibrosis in ABCB4-deficient mice

et al. 2014

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“…This observation could be explained, at least in part, by interactions between vitamin D and bile acid metabolism. Circulating bile acids levels are about ten-fold higher in Abcb4 −/− as compared to wild-type mice (not shown) and in fact, the secondary bile acid lithocholic acid (LCA) is known to have deleterious effects on osteoblasts viability and affect the expression of Bglap and Rankl [47, 48]. Moreover, the treatment with LCA in combination with vitamin D decreases the expression of Cyp24a1 , encoding the hydroxylase involved in catabolism of vitamin D. Additionally to bile acids, elevated serum bilirubin in the ABCB4 deficient mouse model [24] could also affect bone formation since unconjugated bilirubin is known to impair osteoblast proliferation in a dose-dependent fashion [34].…”

Section: Discussionmentioning

confidence: 99%

Modeling hepatic osteodystrophy in Abcb4 deficient mice

Hochrath

Ehnert

Ackert‐Bicknell

et al. 2013

Bone

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Hepatic osteodystrophy (HOD) denotes the alterations in bone morphology and metabolism frequently observed in patients with chronic liver diseases, in particular in case of cholestatic conditions. The molecular mechanisms underlying HOD are only partially understood. In the present study, we characterized the bone phenotypes of the ATP-binding cassette transporter B4 knockout mouse (Abcb4−/−), a well-established mouse model of chronic cholestatic liver disease, with the aim of identifying and characterizing a mouse model for HOD. Furthermore, we investigated the influence of vitamin D on bone quality in this model. The bone morphology analyses revealed reduced bone mineral contents as well as changes in trabecular bone architecture and decreased cortical bone densities in Abcb4−/− mice with severe liver fibrosis. We observed dysregulation of genes involved in bone remodeling (osteoprotegerin, osteocalcin, osteopontin) and vitamin D metabolism (7-dehydrocholesterol reductase, Gc-globulin, Cyp2r1, Cyp27a1) as well as alterations in calcium and vitamin D homeostasis. In addition, serum RANKL and TGF-β levels were increased in Abcb4−/− mice. Vitamin D dietary intervention was only partially able to restore the bone phenotypes of Abcb4−/− animals. We conclude that the Abcb4−/− mouse provides an experimental framework and a preclinical model to gain further insights into the molecular pathobiology of HOD and to study the systemic effects of therapeutic interventions.

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“…125 Its pathogenesis is poorly understood, but it mainly results from low bone formation as a consequence of cholestasis on osteoblasts. 126 Increased bone resorption has also been described in women with advanced disease.…”

Section: Osteoporosismentioning

confidence: 97%

Old and Novel Therapies for Primary Biliary Cirrhosis

Parés

2014

Semin Liver Dis

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Despite the presumed immunological pathogenesis of primary biliary cirrhosis, no clear or even harmful consequences resulted from some specific treatments addressed to modify the immunological condition. However, ursodeoxycholic acid (UDCA; 13-16 mg/kg/d) has clear favorable effects not only by improving biochemical cholestasis, but also by delaying the histological progression. Long -term treatment with UDCA is associated with excellent survival, free of transplantation in cases showing biochemical response at one year. In the remaining patients, data on the effect of fibrates, budesonide, or obeticholic acid are encouraging. Pruritus is usually managed using resins; further steps are needed in resistant cases with the use of rifampicin, naltrexone, sertraline, or invasive procedures such as albumin dialysis. Osteoporosis, which is highly prevalent in patients with deep and prolonged cholestasis, improves with bisphosphonates; current data indicate that both weekly alendronate and monthly ibandronate increase bone mass in patients with osteoporosis. Nutritional and fat-vitamin supplementation is also mandatory in patients with severe cholestasis.

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Lithocholic acid downregulates vitamin D effects in human osteoblasts

Cited by 61 publications

References 46 publications

Vitamin D modulates biliary fibrosis in ABCB4-deficient mice

Vitamin D modulates biliary fibrosis in ABCB4-deficient mice

Modeling hepatic osteodystrophy in Abcb4 deficient mice

Old and Novel Therapies for Primary Biliary Cirrhosis

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