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 4

Acute liver failure is efficiently avoided by a short-term in vivo treatment with MB.

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Acute liver failure is efficiently avoided by a short-term in vivo treat...
(A) Overt liver damage was reduced in MB-treated but not D-PA– or TETA-treated Atp7b–/– livers. Scale bars: 100 μm; H&E staining (symbols as in Figure 1 and Supplemental Figure 1). Daily doses were: 150 mg (130 μmol) MB/kg BW; 100 mg (540 μmol) D-PA/kg BW; and 480 mg (2,190 μmol) TETA/kg BW. Three-day MB treatment: 2 experiments; 5-day MB treatment: 5 experiments; D-PA and TETA treatments: 4 experiments. (B) AST values decreased in 2 of 3 and 4 of 6 Atp7b–/– rats treated for 3 or 5 days with MB, respectively, but not in untreated Atp7b–/– (N = 6 [3 affected and 3 diseased]) or short-term D-PA– or TETA-treated rats (N = 6 [3 affected and 3 diseased]). Treatment started in rats at 82–90 days of age. (C) Mild reduction of whole-liver and significant reduction of mitochondrial copper level in short-term MB-treated rats (3-day MB treatment, N = 3 [2 affected and 1 disease onset], aged 88–89 days; 5-day MB treatment, N = 5 [5 affected], aged 89–95 days) but not in untreated rats (N = 4 [2 affected, 2 diseased], aged 90–91 days) or D-PA– or TETA-treated rats (N = 4 [3 affected, 1 disease onset], aged 86–89 days). One-way ANOVA with Tukey’s multiple comparisons test. *P < 0.05 versus untreated controls. (D) Massively reduced numbers in mitochondria with severely impaired structure (type 4, arrows) were isolated from MB-treated rats but not from untreated (Figure 2A) or D-PA– or TETA-treated Atp7b–/– rats (quantification in Supplemental Figure 4A). Scale bars: 1 μm. (E) Treatment of Atp7b+/– control rats with MB (i.p. once daily on 2 consecutive days; N = 4) did not change whole-liver or mitochondrial copper levels. Untreated control, N = 3. (F) Upon i.p. injection, MB was only detectable in the serum for half an hour, indicating a very short systemic residence time (n = 2). U, untreated.