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Lichtmannegger, J. ; Leitzinger, C. ; Wimmer, R.* ; Schmitt, S. ; Schulz, S. ; Kabiri, Y. ; Eberhagen, C. ; Rieder, T.* ; Janik, D. ; Neff, F. ; Straub, B.K.* ; Schirmacher, P.* ; DiSpirito, A.A.* ; Bandow, N.* ; Baral, B.S.* ; Flatley, A. ; Kremmer, E. ; Denk, G.U.* ; Reiter, F.P.* ; Hohenester, S.* ; Eckardt-Schupp, F. ; Dencher, N.A.* ; Adamski, J. ; Sauer, V.* ; Niemietz, C.* ; Schmidt, H.H.* ; Merle, U.* ; Gotthardt, D.N.* ; Kroemer, G.* ; Weiss, K.H.* ; Zischka, H.

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

J. Clin. Invest. 126, 2721-2735 (2016)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Methylosinus-trichosporium Ob3b; Methane-oxidizing Bacteria; D-penicillamine Prevents; Permeability Transition; Copper-acquisition; Cinnamon Rats; Gene-therapy; Mitochondrial; Transplantation; Cells
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 126, Issue: 7, Pages: 2721-2735 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place Ann Arbor
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOX)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Pathology (PATH)
Institute of Molecular Immunology (IMI)
Institute of Radiation Biology (ISB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30201 - Metabolic Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30202 - Environmental Health
Research field(s) Enabling and Novel Technologies
Genetics and Epidemiology
Immune Response and Infection
Radiation Sciences
PSP Element(s) G-505200-003
G-505200-001
G-505600-001
G-500300-001
G-501793-001
G-500200-001
DOI 10.1172/JCI85226
WOS ID WOS:000379094800032
Scopus ID 84978412130
PubMed ID 27322060
Erfassungsdatum 2016-07-04
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