norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis

Fickert, Peter; Hirschfield, Gideon M.; Denk, Gerald; Marschall, Hanns‐Ulrich; Altorjay, István; Färkkilä, Martti; Schramm, Christoph; Spengler, Ulrich; Chapman, Roger W.; Bergquist, Annika; Schrumpf, E.; Nevens, Frederik; Trivedi, Palak; Reiter, Florian P.; Tornai, István; Halilbasic, Emina; Greinwald, Roland; Pröls, Markus; Manns, Michael P.; Trauner, Michael

doi:10.1016/j.jhep.2017.05.009

Cited by 207 publications

(167 citation statements)

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“…Several studies using NorUDCA treatment in murine models of cholestasis, and a recently conducted phase II human clinical trial, support the benefits of this drug as a treatment option for cholestatic patients . In our present work, we show that NorUDCA modulates SIRT1 expression in two alternative models of cholestasis: in SIRT oe mice after BDL and in Mdr2 –/– mice.…”

Section: Discussionsupporting

confidence: 76%

“…NorUDCA has proven efficacy in treating murine cholestasis in Mdr2 –/– mice and improving cholestasis in PSC patients . We previously described that NorUDCA reduced SIRT1 expression in noncholestatic SIRT oe mice, which associated with an improved response to injury and restored regenerative capacity of the liver .…”

Section: Resultsmentioning

confidence: 94%

“…Current therapeutic approaches for treating cholestasis mainly rely on the use of ursodeoxycholic acid (UDCA); however, this treatment has no proven efficacy for PSC and a proportion of patients with PBC . The therapeutic options for such unresponsive patients are currently limited, though there have been recent promising advances, including the use of 24‐norursodeoxycholic acid (NorUDCA), which has been shown to improve liver function in PSC patients in a recent clinical trial . Also, novel treatments using fibrates and farnesoid X receptor (FXR) agonists, such as obeticholic acid, have shown efficacy for PBC patients unresponsive to UDCA.…”

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confidence: 99%

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Fine‐Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease

et al. 2019

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Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1‐overexpressing (SIRT oe ) and hepatocyte‐specific SIRT1‐KO (knockout) mice ( SIRT hep–/– ) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24‐norursodeoxycholic acid) was tested in BDL/SIRT oe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice ( Mdr2 –/– ) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro . SIRT oe mice showed exacerbated parenchymal injury whereas SIRT hep–/– mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRT oe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRT hep–/– hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRT oe mice. Interestingly, both SIRT1 overexpression and hepatocyte‐specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling. Conclusion: SIRT1 expression is increased during human and murine cholestasis. Fine‐tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage.

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 94%

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confidence: 99%

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Fine‐Tuning of Sirtuin 1 Expression Is Essential to Protect the Liver From Cholestatic Liver Disease

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“…Several new agents are currently being tested in cholestatic and fibrotic liver diseases in adults (Table ). These include bile acid–based therapeutics such as the farnesoid X receptor (FXR) agonist obeticholic acid in primary biliary cholangitis and the modified bile acid norursodeoxycholic acid, which is currently in phase 2 trials in adult primary sclerosing cholangitis . FXR agonists suppress bile acid synthesis and engage multiple anticholestatic adaptive responses in liver, while norursodeoxycholic acid reduces markers of cholangiocyte damage, suggesting that one, or both, agents might be beneficial in BA.…”

Section: Innovative Approaches To Treatmentmentioning

confidence: 99%

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

et al. 2018

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Biliary atresia (BA) is a fibroinflammatory disease of the intra- and extrahepatic biliary tree. Without medical treatment, surgical hepatic portoenterosmy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a pre-natal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g. biliatresone) and of viruses (e.g. CMV) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate pro-inflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following an epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. This article is protected by copyright. All rights reserved.

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“…There exist more anticholestatic compounds, which in contrast to the aforementioned drugs, do not possess multiple anticholestatic properties but show a single very potent anticholestatic feature. NorUDCA is the most powerful inducer of bicarbonate‐rich biliary hypercholeresis to protect bile ducts, and has shown promising effects in a phase II clinical PSC trial . FGF19 mimetics potently reduce bile acid synthesis (trial and ) .…”

Section: Why Do We Need Additional Therapy?mentioning

confidence: 99%