Methanobactin reverses acute liver failure in a rat model of Wilson disease
Josef Lichtmannegger, … , Karl Heinz Weiss, Hans Zischka
Josef Lichtmannegger, … , Karl Heinz Weiss, Hans Zischka
Published June 20, 2016
Citation Information: J Clin Invest. 2016;126(7):2721-2735. https://doi.org/10.1172/JCI85226.
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Research Article Gastroenterology Hepatology

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

Abstract

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 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.

Authors

Josef Lichtmannegger, Christin Leitzinger, Ralf Wimmer, Sabine Schmitt, Sabine Schulz, Yaschar Kabiri, Carola Eberhagen, Tamara Rieder, Dirk Janik, Frauke Neff, Beate K. Straub, Peter Schirmacher, Alan A. DiSpirito, Nathan Bandow, Bipin S. Baral, Andrew Flatley, Elisabeth Kremmer, Gerald Denk, Florian P. Reiter, Simon Hohenester, Friedericke Eckardt-Schupp, Norbert A. Dencher, Jerzy Adamski, Vanessa Sauer, Christoph Niemietz, Hartmut H.J. Schmidt, Uta Merle, Daniel Nils Gotthardt, Guido Kroemer, Karl Heinz Weiss, Hans Zischka

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Figure 5

Short-term MB treatments postpone acute liver failure.

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Short-term MB treatments postpone acute liver failure. (A) Short-term (5...
(A) Short-term (5 days) MB-treated Atp7b–/– rats (animal age at start of treatment: 84–85 days) remained healthy for at least 2 weeks, after which serum AST and bilirubin (not shown) levels rose again. At the time of analysis, 1 animal (Atp7b–/– rat 1) was still healthy, and 2 animals (Atp7b–/– rats 2 and 3) were diseased. (B–D) In the order of Atp7b–/– rats 1 to 3, respectively, mitochondrial copper content was elevated but not the whole-liver copper content (B), the frequency of the typical histological features of overt liver damage increased (C, symbols as in Figure 1 and Supplemental Figure 1), and the severity of mitochondrial structure impairments increased (D, arrows). Scale bars: 100 μm (C) and 500 nm (D).