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Methanobactin reverses acute liver failure in a rat model of Wilson disease.

ABSTRACT: In Wilson disease (WD), functional loss of ATPase copper-transporting ? (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD.

SUBMITTER: Lichtmannegger J

PROVIDER: S-EPMC4922707 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Methanobactin reverses acute liver failure in a rat model of Wilson disease.

Lichtmannegger Josef J Leitzinger Christin C Wimmer Ralf R Schmitt Sabine S Schulz Sabine S Kabiri Yaschar Y Eberhagen Carola C Rieder Tamara T Janik Dirk D Neff Frauke F Straub Beate K BK Schirmacher Peter P DiSpirito Alan A AA Bandow Nathan N Baral Bipin S BS Flatley Andrew A Kremmer Elisabeth E Denk Gerald G Reiter Florian P FP Hohenester Simon S Eckardt-Schupp Friedericke F Dencher Norbert A NA Adamski Jerzy J Sauer Vanessa V Niemietz Christoph C Schmidt Hartmut H J HH Merle Uta U Gotthardt Daniel Nils DN Kroemer Guido G Weiss Karl Heinz KH Zischka Hans H

The Journal of clinical investigation 20160620 7

In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the ...[more]

PMID: 27322060

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Project description:Acute liver failure (ALF) is a rare but devastating disease associated with substantial morbidity and a mortality rate of almost 45%. Medical treatments, apart from supportive care, are limited and liver transplantation may be the only rescue option. Large animal models, which most closely represent human disease, can be logistically and technically cumbersome, expensive and pose ethical challenges. The development of isolated organ perfusion technologies, originally intended for preservation before transplantation, offers a new platform for experimental models of liver disease, such as ALF. In this study, female domestic swine underwent hepatectomy, followed by perfusion of the isolated liver on a normothermic machine perfusion device. Five control livers were perfused for 24 h at 37 °C, while receiving supplemental oxygen and nutrition. Six livers received toxic doses of acetaminophen given over 12 h, titrated to methemoglobin levels. Perfusate was sampled every 4 h for measurement of biochemical markers of injury (e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT]). Liver biopsies were taken at the beginning, middle, and end of perfusion for histological assessment. Acetaminophen-treated livers received a median dose of 8.93 g (8.21-9.75 g) of acetaminophen, achieving a peak acetaminophen level of 3780 µmol/L (3189-3913 µmol/L). Peak values of ALT (76 vs. 105 U/L; p = 0.429) and AST (3576 vs. 4712 U/L; p = 0.429) were not significantly different between groups. However, by the end of perfusion, histology scores were significantly worse in the acetaminophen treated group (p = 0.016). All acetaminophen treated livers developed significant methemoglobinemia, with a peak methemoglobin level of 19.3%, compared to 2.0% for control livers (p = 0.004). The development of a model of ALF in the ex vivo setting was confounded by the development of toxic methemoglobinemia. Further attempts using alternative agents or dosing strategies may be warranted to explore this setting as a model of liver disease.

Dataset Information

Methanobactin reverses acute liver failure in a rat model of Wilson disease.

Publications

Methanobactin reverses acute liver failure in a rat model of Wilson disease.

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