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A Case for Not Going Global: “Americanization” of Diet Accelerates Hepatic Mitochondrial Injury in a Model of Wilson Disease

  • Uyen To
    Affiliations
    Departments of Medicine and Surgery, Divisions of Digestive Diseases and Transplant and Immunology, Yale University, New Haven, Connecticut
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  • Michael L. Schilsky
    Correspondence
    Correspondence Address correspondence to: Michael L. Schilsky, MD, Yale University Medical Center, Departments of Medicine and Surgery, Divisions of Digestive Diseases Transplant and Immunology, 333 Cedar Street, LMP 1080, New Haven, Connecticut 06511. fax: (212) 746-8974.
    Affiliations
    Departments of Medicine and Surgery, Divisions of Digestive Diseases and Transplant and Immunology, Yale University, New Haven, Connecticut
    Search for articles by this author
Open AccessPublished:January 29, 2019DOI:https://doi.org/10.1016/j.jcmgh.2019.01.001
      Perhaps globalization is not always best, and we should avoid exporting the unhealthy diet responsible for the “American lifestyle induced obesity syndrome” that negatively impacts liver health. Adopt this unhealthy diet and add a sprinkle of copper, and you have a recipe for worsening liver disease. Einer et al
      • 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-calorie diet aggravates mitochondrial dysfunction and triggers severe liver damage in Wilson disease rats.
      gave the equivalent of the American lifestyle high-caloric diet to a rodent model of Wilson disease (WD), and bad things happened. There was increased oxidative stress, promotion of mitochondrial and hepatocellular injury, and earlier-onset liver disease. Proof that copper is the “accelerant” in this model comes from its effects on hepatic mitochondria, where it caused enhanced beta oxidation and breakdown of fatty acids, increased acetyl CoA and cytosolic triglycerides, impaired adenosine triphosphate production, increased hydrogen peroxide production, and elevated synthesis of cholesterol and bile salts.
      • 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-calorie diet aggravates mitochondrial dysfunction and triggers severe liver damage in Wilson disease rats.
      Copper is an essential element required for neurotransmitter and collagen biosynthesis, angiogenesis, wound healing, and iron utilization.
      • Kaplan J.H.
      • Maryon E.B.
      How mammalian cells acquire copper: an essential but potentially toxic metal.
      Prosthetic copper in cytochrome c oxidase and in Cu/Zn superoxide dismutase (SOD) is critical for their function. Both cytochrome oxidase and SOD2 are localized to mitochondria, and their enzymatic activity modulates reactive oxygen species within cells.
      • Blockhuys S.
      • Celauro E.
      • Hildesjö C.
      • Feizi A.
      • Stål O.
      • Fierro-González J.C.
      • Wittung-Stafshede P.
      Defining the human copper proteome and analysis of its expression variation in cancers.
      The mitochondria are a target for oxidative injury in copper overloaded states. In WD, excess copper leads to structural changes within hepatocellular mitochondria, including organelle elongations and cristae dilatations.
      • Zischka H.
      • Lichtmannegger J.
      • Schmitt S.
      • Jägemann N.
      • Schulz S.
      • Wartini D.
      • Jennen L.
      • Rust C.
      • Larochette N.
      • Galluzzi L.
      • Chajes V.
      • Bandow N.
      • Gilles V.S.
      • DiSpirito A.A.
      • Esposito I.
      • Goettlicher M.
      • Summer K.H.
      • Kroemer G.
      Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease.
      The extent of structural damage to mitochondria directly correlates with the degree of copper overload.
      • Zischka H.
      • Lichtmannegger J.
      • Schmitt S.
      • Jägemann N.
      • Schulz S.
      • Wartini D.
      • Jennen L.
      • Rust C.
      • Larochette N.
      • Galluzzi L.
      • Chajes V.
      • Bandow N.
      • Gilles V.S.
      • DiSpirito A.A.
      • Esposito I.
      • Goettlicher M.
      • Summer K.H.
      • Kroemer G.
      Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease.
      Copper accumulation in mitochondria leads to emergence of reactive oxygen species and disintegration of the mitochondrial membrane, signaling cell death.
      • Sokol R.J.
      • Twedt D.
      • McKim Jr, J.M.
      • Devereaux M.W.
      • Karrer F.M.
      • Kam I.
      • von Steigman G.
      • Narkewicz M.R.
      • Bacon B.R.
      • Britton R.S.
      • et al.
      Oxidant injury to hepatic mitochondria in patients with Wilson's disease and Bedlington terriers with copper toxicosis.
      Further supporting the role of mitochondrial damage in the pathogenesis of WD is the successful use of chelation therapy with D-penicillamine in reversing mitochondrial abnormalities.
      • Scheinberg I.H.
      • Sternlieb I.
      • Schilsky M.
      • Stockert R.J.
      Penicillamine may detoxify copper in Wilson's disease.
      Conversely, in individuals who failed to respond to chelation therapy, their hepatic mitochondria still had significant amounts of copper overload and structural changes.
      • Sokol R.J.
      • Twedt D.
      • McKim Jr, J.M.
      • Devereaux M.W.
      • Karrer F.M.
      • Kam I.
      • von Steigman G.
      • Narkewicz M.R.
      • Bacon B.R.
      • Britton R.S.
      • et al.
      Oxidant injury to hepatic mitochondria in patients with Wilson's disease and Bedlington terriers with copper toxicosis.
      Methanobactin, a post-translational modified peptide from a proteobacterium Methylosinus trichosporium, has a high copper binding affinity and therefore was used previously, and again in this study by Einer et al,
      • 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-calorie diet aggravates mitochondrial dysfunction and triggers severe liver damage in Wilson disease rats.
      to chelate mitochondrial copper. It was able to achieve this effect because methanobactin is permeable through the mitochondrial membrane and can remove excess mitochondrial copper better than D-penicillamine or trientene.
      • Vita N.
      • Platsaki S.
      • Baslé A.
      • Allen S.J.
      • Paterson N.G.
      • Crombie A.T.
      • Murrell J.C.
      • Waldron K.J.
      • Dennison C.
      A four-helix bundle stores copper for methane oxidation.
      Lichtmannegger et al
      • 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.
      • 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.
      showed that treatment of ATP7b–/– rats with methanobactin reduced mitochondrial copper, restored mitochondrial structure and function, and lacked liver damage. Studies have suggested that changes in mitochondrial copper content, structure, and functionality play a pivotal role in early response to chelation treatment and potentially predict response or progression of liver disease.
      • 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.
      • 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.
      Thus, “happy” mitochondria are a key ingredient in the recipe for successful rescue of copper toxicity, and “unhappy” injured mitochondria portend disease progression or treatment failure.
      Hepatic steatosis seen in WD is thought to be directly related to copper overload and copper toxicity, in particular to the mitochondria of hepatocytes.
      • Ludwig J.
      • Moyer T.P.
      • Rakela J.
      The liver biopsy diagnosis of Wilson’s disease: methods in pathology.
      There have been a few studies suggesting an indirect link between copper overload and steatosis, with steatosis occurring with other environmental exposures.
      • Lutsenko S.
      Modifying factors and phenotypic diversity in Wilson's disease.
      One potential influence could be a dysregulation of lipids in patients with WD. Mutations in the apolipoprotein genes APOEε3 and APOEε4 were associated with liver disease, and lower levels of serum cholesterol were seen in some WD patients.
      • Litwin T.
      • Gromadzka G.
      • Czlonkowska A.
      Apolipoprotein E gene (APOE) genotype in Wilson's disease: impact on clinical presentation.
      In a study by Stattermayer et al,
      • Stattermayer A.F.
      • Traussnigg S.
      • Dienes H.P.
      • Aigner E.
      • Stauber R.
      • Lackner K.
      • Hofer H.
      • Stift J.
      • Wrba F.
      • Stadlmayr A.
      • Datz C.
      • Strasser M.
      • Maieron A.
      • Trauner M.
      • Ferenci P.
      Hepatic steatosis in Wilson disease: role of copper and PNPLA3 mutations.
      the presence of PNPLA3 G genotype was thought to contribute to steatosis in WD patients. They found that age and PNPLA3 G genotype had a significant impact on the presence of hepatic steatosis, but hepatic copper content did not. However, PNPLA3 G genotype was also associated with mitochondrial dysfunction, again pointing toward the pivotal role of hepatic mitochondria in WD.
      • Min H.K.
      • Sookoian S.
      • Pirola C.J.
      • Cheng J.
      • Mirshahi F.
      • Sanyal A.J.
      Metabolic profiling reveals that PNPLA3 induces widespread effects on metabolism beyond triacylglycerol remodeling in Huh-7 hepatoma cells.
      The plasticity of the mitochondria, compartmentalization of copper in the mitochondria, and other environmental factors could partially explain the wide range of phenotypic differences in WD.
      Some of the critical, but yet unanswered, questions raised by these ideas include whether aggressive copper chelation therapy before exposure to a high-calorie diet could mitigate the injury, and whether a combination of a low fat and fructose diet in addition to efforts to reduce hepatic copper could prevent progression of WD. If this were to occur, then we may place an increased emphasis on “decoppering” and intensive dietary counseling to prevent further mitochondrial injury. Perhaps then we can begin to change the “recipe” and start to shift the copper balance in favor of our patients.

      References

        • 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-calorie diet aggravates mitochondrial dysfunction and triggers severe liver damage in Wilson disease rats.
        Cell Mol Gastroenterol Hepatol. 2019; 7: 571-596
        • Kaplan J.H.
        • Maryon E.B.
        How mammalian cells acquire copper: an essential but potentially toxic metal.
        Biophys J. 2016; 110: 7-13
        • Blockhuys S.
        • Celauro E.
        • Hildesjö C.
        • Feizi A.
        • Stål O.
        • Fierro-González J.C.
        • Wittung-Stafshede P.
        Defining the human copper proteome and analysis of its expression variation in cancers.
        Metallomics. 2017; 9: 112-123
        • Zischka H.
        • Lichtmannegger J.
        • Schmitt S.
        • Jägemann N.
        • Schulz S.
        • Wartini D.
        • Jennen L.
        • Rust C.
        • Larochette N.
        • Galluzzi L.
        • Chajes V.
        • Bandow N.
        • Gilles V.S.
        • DiSpirito A.A.
        • Esposito I.
        • Goettlicher M.
        • Summer K.H.
        • Kroemer G.
        Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease.
        J Clin Invest. 2011; 121: 1508-1518
        • Sokol R.J.
        • Twedt D.
        • McKim Jr, J.M.
        • Devereaux M.W.
        • Karrer F.M.
        • Kam I.
        • von Steigman G.
        • Narkewicz M.R.
        • Bacon B.R.
        • Britton R.S.
        • et al.
        Oxidant injury to hepatic mitochondria in patients with Wilson's disease and Bedlington terriers with copper toxicosis.
        Gastroenterology. 1994; 107: 1788-1798
        • Scheinberg I.H.
        • Sternlieb I.
        • Schilsky M.
        • Stockert R.J.
        Penicillamine may detoxify copper in Wilson's disease.
        Lancet. 1987; 330: 95
        • Vita N.
        • Platsaki S.
        • Baslé A.
        • Allen S.J.
        • Paterson N.G.
        • Crombie A.T.
        • Murrell J.C.
        • Waldron K.J.
        • Dennison C.
        A four-helix bundle stores copper for methane oxidation.
        Nature. 2015; 525: 140-143
        • 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.
        • 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. 2016; 126: 2721-2735
        • Ludwig J.
        • Moyer T.P.
        • Rakela J.
        The liver biopsy diagnosis of Wilson’s disease: methods in pathology.
        Am J Clin Pathol. 1994; 102: 443-446
        • Lutsenko S.
        Modifying factors and phenotypic diversity in Wilson's disease.
        Ann N Y Acad Sci. 2014; 1315: 56-63
        • Litwin T.
        • Gromadzka G.
        • Czlonkowska A.
        Apolipoprotein E gene (APOE) genotype in Wilson's disease: impact on clinical presentation.
        Parkinsonism Relat Disord. 2012; 18: 367-369
        • Stattermayer A.F.
        • Traussnigg S.
        • Dienes H.P.
        • Aigner E.
        • Stauber R.
        • Lackner K.
        • Hofer H.
        • Stift J.
        • Wrba F.
        • Stadlmayr A.
        • Datz C.
        • Strasser M.
        • Maieron A.
        • Trauner M.
        • Ferenci P.
        Hepatic steatosis in Wilson disease: role of copper and PNPLA3 mutations.
        J Hepatol. 2015; 63: 156-163
        • Min H.K.
        • Sookoian S.
        • Pirola C.J.
        • Cheng J.
        • Mirshahi F.
        • Sanyal A.J.
        Metabolic profiling reveals that PNPLA3 induces widespread effects on metabolism beyond triacylglycerol remodeling in Huh-7 hepatoma cells.
        Am J Physiol Gastrointest Liver Physiol. 2014; 307: G66-G76

      Linked Article

      • A High-Calorie Diet Aggravates Mitochondrial Dysfunction and Triggers Severe Liver Damage in Wilson Disease Rats
        Cellular and Molecular Gastroenterology and HepatologyVol. 7Issue 3
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          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.
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