Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health

Dilger, Karin; Hohenester, Simon; Winkler-Budenhofer, Ursula; Bastiaansen, Barbara A.; Schaap, Frank G.; Rust, Christian; Beuers, Ulrich

doi:10.1016/j.jhep.2012.02.014

Cited by 106 publications

(96 citation statements)

References 35 publications

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“…52-54 UDCA has potent anticholestatic and antiapoptotic properties and is enriched from 1-2% to ~40% of total bile acids in the The study was designed to examine whether modulation of the immune system by treating patients with high dose cyclophosphamide, fludarabine and CAMPATH-1H, followed by return of blood stem cells that have been previously collected from a patient's sibling would stop or reverse the disease The stem cell infusion was to restore blood production after treatment with cyclophosphamide, fludarabine and CAMPATH-1H, and to produce a normal immune system bile of patients with PBC and healthy volunteers treated with therapeutic daily doses of 15 mg/kg body weight. 55 How does UDCA exert its anticholestatic properties at the level of the hepatocyte? In contrast to hydrophobic bile acids of the type seen to predominate in PBC and thought to contribute substantially to bile duct injury, UDCA does not markedly affect transport protein expression in vivo at the transcriptional level to modulate transport capacity.…”

Section: Future Directions In Prognostic Therapymentioning

confidence: 99%

Novel therapeutic targets in primary biliary cirrhosis

Dyson

Hirschfield

Adams

et al. 2015

Nat Rev Gastroenterol Hepatol

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113

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Primary biliary cirrhosis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis. It results in characteristic symptoms with marked effects on life quality. The advent of large patient cohorts has challenged the view of PBC as a benign condition treated effectively by the single licensed therapy-ursodeoxycholic acid (UDCA). UDCA nonresponse or under-response has a major bearing on outcome, substantially increasing the likelihood that liver transplantation will be required or that patients will die of the disease. In patients with high-risk, treatment-unresponsive or highly symptomatic disease the need for new treatment approaches is clear. Evolution in our understanding of disease mechanisms is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. Notable opportunities are offered by targeting what could be considered as the 'upstream' immune response, 'midstream' biliary injury and 'downstream' fibrotic processes. Combination therapy targeting several pathways or the development of novel agents addressing multiple components of the disease pathway might be required. Ultimately, PBC therapeutics will require a stratified approach to be adopted in practice. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.

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Section: Future Directions In Prognostic Therapymentioning

confidence: 99%

Novel therapeutic targets in primary biliary cirrhosis

Dyson

Hirschfield

Adams

et al. 2015

Nat Rev Gastroenterol Hepatol

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113

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“…Under chronic cholestatic conditions, hydrophobic, i.e. potentially toxic, bile salts accumulate in the body [4] and are thought to drive disease progression [2]. Reflecting upon cholangiocellular physiology, it is striking that cholangiocytes are continuously exposed, without major damage, to the most toxic of all body fluids: bile.…”

Section: Toxic Bile Saltsmentioning

confidence: 99%

The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO<sub>3</sub><sup>-</sup> Umbrella': An Integrated Line of Defense against Toxic Bile Acids

Wenniger

Hohenester

Maroni

et al. 2015

Dig Dis

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Background: Destruction of cholangiocytes is the hallmark of chronic cholangiopathies such as primary biliary cirrhosis. Under physiologic conditions, cholangiocytes display a striking resistance to the high, millimolar concentrations of toxic bile salts present in bile. We recently showed that a ‘biliary HCO₃^- umbrella', i.e. apical cholangiocellular HCO₃^- secretion, prevents cholangiotoxicity of bile acids, and speculated on a role for extracellular membrane-bound glycans in the stabilization of this protective layer. This paper summarizes published and thus far unpublished evidence supporting the role of the glycocalyx in stabilizing the ‘biliary HCO₃^- umbrella' and thus preventing cholangiotoxicity of bile acids. Key Messages: The apical glycocalyx of a human cholangiocyte cell line and mouse liver sections were visualized by electron microscopy. FACS analysis was used to characterize the surface glycan profile of cultured human cholangiocytes. Using enzymatic digestion with neuraminidase the cholangiocyte glycocalyx was desialylated to test its protective function. Using lectin assays, we demonstrated that the main N-glycans in human and mouse cholangiocytes were sialylated biantennary structures, accompanied by high expression of the H-antigen (α_1-2 fucose). Apical neuraminidase treatment induced desialylation without affecting cell viability, but lowered cholangiocellular resistance to bile acid-induced toxicity: both glycochenodeoxycholate and chenodeoxycholate (pK_a ≥4), but not taurochenodeoxycholate (pK_a <2), displayed cholangiotoxic effects after desialylation. A 24-hour reconstitution period allowed cholangiocytes to recover to a pretreatment bile salt susceptibility pattern. Conclusion: Experimental evidence indicates that an apical cholangiocyte glycocalyx with glycosylated mucins and other glycan-bearing membrane glycoproteins stabilizes the ‘biliary HCO₃^- umbrella', thus aiding in the protection of human cholangiocytes against bile acid toxicity.

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“…Before secretion from the hepatocytes, all bile acids are conjugated with glycine or taurine at their terminal side chain carboxylic acid group. Although affected by diet and certain cholestatic liver diseases, glycine conjugates dominate in humans (6,7), whereas taurine conjugates dominate in many other species (8,9). Conjugation increases the polarity and hence decreases the lipophilicity (lipophilicity 5 hydrophobicity -polarity) of the bile acids, particularly in the case of conjugation with taurine because of its intrinsically stronger sulfonic acid group compared with the carboxylic acid group of glycine.…”

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confidence: 99%

Radiosynthesis of N-¹¹C-Methyl-Taurine–Conjugated Bile Acids and Biodistribution Studies in Pigs by PET/CT

et al. 2015

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During cholestasis, accumulation of conjugated bile acids may occur in the liver and lead to hepatocellular damage. Inspired by our recent development of N-11 C-methyl-glycocholic acid-that is, 11 C-cholylsarcosine-a tracer for PET of the endogenous glycine conjugate of cholic acid, we report here a radiosynthesis of N-11 C-methyltaurine-conjugated bile acids and biodistribution studies in pigs by PET/CT. Methods: A radiosynthesis of N-11 C-methyl-taurine-conjugated bile acids was developed and used to prepare N-11 C-methyl-taurine conjugates derived from cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, and lithocholic acid. The lipophilicity of these new tracers was determined by reversed-phase thin-layer chromatography. The effect of lipophilicity and structure on the biodistribution was investigated in pigs by PET/CT using the tracers derived from cholic acid (3α-OH, 7α-OH, 12α-OH), ursodeoxycholic acid (3α-OH, 7β-OH), and lithocholic acid (3α-OH). Results: The radiosyntheses of the N-11 C-methyl-taurine-conjugated bile acids proceeded with radiochemical yields of 61% (decay-corrected) or greater and radiochemical purities greater than 99%. PET/CT in pigs revealed that the tracers were rapidly taken up by the liver and secreted into bile. There was no detectable radioactivity in urine. Significant reflux of N-11 C-methyltaurolithocholic acid into the stomach was observed. Conclusion: We have successfully developed a radiosynthesis of N-11 C-methyl-taurineconjugated bile acids. These tracers behave in a manner similar to endogenous taurine-conjugated bile acids in vivo and are thus promising for functional PET of patients with cholestatic diseases.

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Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health

Cited by 106 publications

References 35 publications

Novel therapeutic targets in primary biliary cirrhosis

Novel therapeutic targets in primary biliary cirrhosis

The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO<sub>3</sub><sup>-</sup> Umbrella': An Integrated Line of Defense against Toxic Bile Acids

Radiosynthesis of N-¹¹C-Methyl-Taurine–Conjugated Bile Acids and Biodistribution Studies in Pigs by PET/CT

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Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health

Cited by 106 publications

References 35 publications

Novel therapeutic targets in primary biliary cirrhosis

Novel therapeutic targets in primary biliary cirrhosis

The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO<sub>3</sub><sup>-</sup> Umbrella': An Integrated Line of Defense against Toxic Bile Acids

Radiosynthesis of N-11C-Methyl-Taurine–Conjugated Bile Acids and Biodistribution Studies in Pigs by PET/CT

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Radiosynthesis of N-¹¹C-Methyl-Taurine–Conjugated Bile Acids and Biodistribution Studies in Pigs by PET/CT