Einer 2018 Cell Mol Gastroenterol Hepatol

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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 EV, Polishchuk RS, Hauck SM, von Toerne C, Müller JC, Karst U, Baral BS, DiSpirito AA, Kremer AE, Semrau J, Weiss KH, Hohenester S, Zischka H (2018) A high calorie diet aggravates mitochondrial dysfunction and triggers severe liver damage in Wilson disease rats. Cell Mol Gastroenterol Hepatol 7:571-96.

» PMID: 30586623 Open Access

Einer C, Leitzinger C, Lichtmannegger J, Eberhagen C, Rieder T, Borchard S, Wimmer R, Denk G, Popper B, Neff F, Polishchuk EV, Polishchuk RS, Hauck SM, von Toerne C, Mueller JC, Karst U, Baral BS, DiSpirito AA, Kremer AE, Semrau J, Weiss KH, Hohenester S, Zischka H (2018) Cell Mol Gastroenterol Hepatol

Abstract: 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 negatively affected both by copper overload and steatosis. Therefore, we addressed the question whether a steatosis-promoting high calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage.

Control Atp7b+/- and Wilson disease Atp7b-/- rats were either fed a high calorie Western diet (HCD) or a normal diet (ND). Copper chelation using the high-affinity peptide Methanobactin was employed in HCD-fed Atp7b-/- rats to test for therapeutic reversal of mitochondrial copper damage.

In comparison to a ND, HCD feeding of Atp7b-/- rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly elevated mitochondrial copper accumulation was observed in HCD-fed Atp7b-/- rats, correlating with severe liver injury. Mitochondria presented with massive structural damage, elevated H2O2 emergence and dysfunctional ATP production. Hepatocellular injury was presumably augmented due to oxidative stress. Reduction of mitochondrial copper by Methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage.

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.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: Copper-storage disease, Methanobactin, Mitochondria, Steatohepatitis, Steatosis Bioblast editor: Plangger M O2k-Network Lab: DE Munich Zischka H


Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style  Pathology: Inherited 

Organism: Rat  Tissue;cell: Liver  Preparation: Isolated mitochondria  Enzyme: Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS, ET  Pathway:HRR: Oxygraph-2k 

Labels, 2019-01