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Einer, C. ; Leitzinger, C. ; Lichtmannegger, J. ; Eberhagen, C. ; Rieder, T.* ; Borchard, S. ; Wimmer, R.* ; Denk, G.* ; Popper, B.* ; Neff, F. ; Polishchuk, E.V.* ; Polishchuk, R.S.* ; Hauck, S.M. ; von Toerne, C. ; Müller, J.C.* ; Karst, U.* ; Baral, B.S.* ; DiSpirito, A.A.* ; Kremer, A.E.* ; Semrau, J.* ; Weiss, K.H.* ; Hohenester, S.* ; Zischka, H.

A high caloric diet aggravates mitochondrial dysfunction and triggers severe liver damage in Wilson disease rats.

Cell. Mol. Gast. Hept. 7, 571-596 (2019)
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BACKGROUND & AIMS: In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage.METHODS: Control Atp7b(+/-) and Wilson disease Atp7b(-/-) rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b(-/-) rats to test for therapeutic reversal of mitochondrial copper damage.RESULTS: In comparison with a normal diet, HCD feeding of Atp7b(-/-) rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b(-/-) rats, correlating with severe liver injury. Mitochondria presentedwith massive structural damage, increased H2O2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage.CONCLUSIONS: A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Copper-storage Disease ; Steatosis ; Steatohepatitis ; Mitochondria ; Methanobactin; Nonalcoholic Fatty Liver; Intact Mitochondria; Lipid-metabolism; Atp Homeostasis; Vitamin-e; Copper; Serum; Model; Steatohepatitis; Methanobactin
Language english
Publication Year 2019
Prepublished in Year 2018
HGF-reported in Year 2018
ISSN (print) / ISBN 2352-345X
e-ISSN 2352-345X
Journal Cellular and Molecular Gastroenterology and Hepatology
Quellenangaben Volume: 7, Issue: 3, Pages: 571-596 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOX)
Institute of Experimental Genetics (IEG)
CF Metabolomics & Proteomics (CF-MPC)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30201 - Metabolic Health
Research field(s) Enabling and Novel Technologies
Genetics and Epidemiology
PSP Element(s) G-505200-003
G-505200-001
G-500600-001
G-505700-001
DOI 10.1016/j.jcmgh.2018.12.005
WOS ID WOS:000465010500006
Scopus ID 85062430394
PubMed ID 30586623
Erfassungsdatum 2019-01-08
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