Hepatic steatosis in Wilson disease – Role of copper and PNPLA3 mutations

Stättermayer, Albert Friedrich; Traussnigg, Stefan; Dienes, Hans‐Peter; Aigner, Elmar; Stauber, Rudolf; Lackner, K; Hofer, Harald; Stift, Judith; Wrba, Friedrich; Stadlmayr, Andreas; Datz, Christian; Straßer, Michael; Maieron, A; Trauner, Michael; Ferenci, Péter

doi:10.1016/j.jhep.2015.01.034

Cited by 91 publications

(68 citation statements)

References 50 publications

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“…56 A hallmark of WD is hepatic fat accumulation; therefore, the prevalence of PNPLA3 mutations was investigated in 98 patients with WD. 22 Multivariate logistic regression revealed the PNPLA3 G allele was an independent variable associated with moderate/severe steatosis, whereas hepatic copper content was not. 22 …”

Section: Potential Modifier Genesmentioning

confidence: 99%

“…22 Multivariate logistic regression revealed the PNPLA3 G allele was an independent variable associated with moderate/severe steatosis, whereas hepatic copper content was not. 22 …”

Section: Potential Modifier Genesmentioning

confidence: 99%

“…20,21 Over 500 mutations in ATP7B have been identified, 380 of which have been deemed to be disease-causing mutations. 22 Most of these changes are missense mutations, small insertions and deletions in the coding region, or splice junction mutations. Whole-exon deletions, mutations in the promoter region, and multiple mutations within the same gene also occur but are less common (for a recent review 23 ).…”

Section: Genetics Of Wilson Diseasementioning

confidence: 99%

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Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Kieffer

Medici

2017

Liver Research

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Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the “multi-hit” hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent “hits” are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.

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Section: Potential Modifier Genesmentioning

confidence: 99%

“…22 Multivariate logistic regression revealed the PNPLA3 G allele was an independent variable associated with moderate/severe steatosis, whereas hepatic copper content was not. 22 …”

Section: Potential Modifier Genesmentioning

confidence: 99%

Section: Genetics Of Wilson Diseasementioning

confidence: 99%

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Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Kieffer

Medici

2017

Liver Research

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“…However, the association with cirrhosis was not replicated in another study that also included patients of European descent [48]. In patients with Wilson disease, carriers of the mutant rs738409[G] allele had a higher prevalence of steatosis [49]. In HIV mono-infected patients, rs738409 [G] has been associated with steatosis, NASH, and fibrosis [50,51].…”

Section: Other Liver Diseasesmentioning

confidence: 99%

PNPLA3 gene in liver diseases

Trépo

Romeo

Zucman‐Rossi

et al. 2016

Journal of Hepatology

231

196

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“…This same redox activity also poses a potential danger, requiring highly orchestrated regulation of copper pools to prevent oxidative stress and free radical damage events that are detrimental to health (12)(13)(14)(15)(16)(17)(18). Indeed, genetic disorders that disrupt copper homeostasis lead to severe and lethal conditions such as Menkes and Wilson's diseases (13,19,20), and imbalances in physiological copper levels and tissue miscompartmentalization arising from genetic and/or dietary factors are correlated with cancer, neurodegenerative diseases, and metabolic disorders such as obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”

mentioning

confidence: 99%

In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

Heffern

Park

Au‐Yeung

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

161

150

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Copper is a required metal nutrient for life, but global or local alterations in its homeostasis are linked to diseases spanning genetic and metabolic disorders to cancer and neurodegeneration. Technologies that enable longitudinal in vivo monitoring of dynamic copper pools can help meet the need to study the complex interplay between copper status, health, and disease in the same living organism over time. Here, we present the synthesis, characterization, and in vivo imaging applications of Copper-Caged Luciferin-1 (CCL-1), a bioluminescent reporter for tissue-specific copper visualization in living animals. CCL-1 uses a selective copper(I)-dependent oxidative cleavage reaction to release d-luciferin for subsequent bioluminescent reaction with firefly luciferase. The probe can detect physiological changes in labile Cu+ levels in live cells and mice under situations of copper deficiency or overload. Application of CCL-1 to mice with liver-specific luciferase expression in a diet-induced model of nonalcoholic fatty liver disease reveals onset of hepatic copper deficiency and altered expression levels of central copper trafficking proteins that accompany symptoms of glucose intolerance and weight gain. The data connect copper dysregulation to metabolic liver disease and provide a starting point for expanding the toolbox of reactivity-based chemical reporters for cell- and tissue-specific in vivo imaging.

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Hepatic steatosis in Wilson disease – Role of copper and PNPLA3 mutations

Cited by 91 publications

References 50 publications

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

PNPLA3 gene in liver diseases

In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

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