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 1

Liver disease in the LPP rat mirrors acute liver failure in WD patients by a devastating mitochondrial copper overload.

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Liver disease in the LPP rat mirrors acute liver failure in WD patients ...
(A) H&E staining of liver damage in diseased Atp7b–/– rats and WD patients with acute liver failure who were either untreated or D-PA treated. Tissue necrosis with resorptive inflammation as well as repair (fibrosis) were detectable (black arrowhead); proliferation of bile ducts (circle), anisokaryosis (black arrow), and several inflammatory infiltrations (white arrow) are marked. Insert shows apoptosis (white asterisk) and nodules with ballooned hepatocytes (black asterisk). Scale bars: 100 μm. (B) Mitochondrial structure impairments in diseased Atp7b–/– rats (top panels) and in WD patients with acute liver failure who were either untreated (middle panels) or D-PA treated (bottom panels). Vacuolization (asterisks) and cristae dilations (arrows), marked differences in electron densities, and separated inner and outer membranes (arrowheads) could be identified. Bottom panels: Some areas had relatively intact mitochondria (top), and others demonstrated severe structural impairments (bottom). Scale bars: 500 nm. (C) Comparable copper burden in whole-liver homogenates and purified liver mitochondria from Atp7b–/– rats and untreated WD patients with acute liver failure (patients 1 and 2). Lower total copper content was detected in tissue homogenates and isolated mitochondria from the livers of WD patients who underwent D-PA treatment. Control Atp7b+/– rats (n = 15); affected Atp7b–/– rats with markedly elevated copper levels but AST levels below 200 U/l and bilirubin levels below 0.5 mg/dl (n = 13); disease-onset Atp7b–/– rats with AST levels above 200 U/l, bilirubin levels below 0.5 mg/dl (n = 8); diseased Atp7b–/– rats with AST levels above 200 U/l and bilirubin levels above 0.5 mg/dl (n = 9). Data were outlier corrected. One-way ANOVA with Tukey’s multiple comparisons test. ****P < 0.0001 versus control; ####P < 0.0001 versus affected; ††††P < 0.0001 versus disease onset.