Lipid and energy metabolism in Wilson disease

Mazi, Tagreed A.; Shibata, Noreene M.; Medici, Valentina

doi:10.1016/j.livres.2020.02.002

Cited by 19 publications

(9 citation statements)

References 151 publications

(179 reference statements)

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“…Recently, gut dysbiosis in WD patients has been settled on a diminished microbial ecosystem with loss of bacterial diversity engaged in transcription factors and ATP-dependent transporters (ABC; ATP-binding cassette) [ 151 ]. Of interest for its implication in the development of hepatic steatosis and inflammation, dysregulation of choline metabolism has been described in WD patients and in the tx-j mice model [ 152 ]. The integrative microbiome and metabolome framework is an amazing research field searching for more specific metabolites acting as messengers between the microbiota and the immune system.…”

Section: The Need For Biomarkers For a Better Diagnosismentioning

confidence: 99%

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

et al. 2021

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Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD’s phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.

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Section: The Need For Biomarkers For a Better Diagnosismentioning

confidence: 99%

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

et al. 2021

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“…Whereas derangements in lipid metabolism are reported in patients with WD 22 , our findings highlight lipidomic dysregulation that is independent of advanced liver disease. These include derangements in fatty acid desaturation and elongation pathways, with lower levels of many very-long-chain fatty acids including behenic acid (22:0), erucic acid (22:1n9), and nervonic acid (24:1n9), which can originate from the denaturation and elongation of palmitic acid (16:0) and stearic acid (18:0).…”

Section: Discussionmentioning

confidence: 45%

The role of intestine in metabolic dysregulation in murine Wilson disease

Sarode

Mazi

Neier

et al. 2023

Preprint

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Background and aims: Major clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, and little is known about other tissues involvement in metabolic changes in WD. In vitro studies suggested that the loss of intestinal ATP7B could contribute to metabolic dysregulation in WD. We tested this hypothesis by evaluating gut microbiota and lipidome in two mouse models of WD and by characterizing a new mouse model with a targeted deletion of Atp7b in intestine. Methods: Cecal content 16S sequencing and untargeted hepatic and plasma lipidome analyses in the Jackson Laboratory toxic-milk and the Atp7b null global knockout mouse models of WD were profiled and integrated. Intestine-specific Atp7b knockout mice (Atp7bΔIEC) was generated using B6.Cg-Tg(Vil1-cre)997Gum/J mice and Atp7bLox/Lox mice, and characterized using targeted lipidome analysis following a high-fat diet challenge. Results: Gut microbiota diversity was reduced in animal models of WD. Comparative prediction analysis revealed amino acid, carbohydrate, and lipid metabolism functions to be dysregulated in the WD gut microbial metagenome. Liver and plasma lipidomic profiles showed dysregulated tri- and diglyceride, phospholipid, and sphingolipid metabolism in WD models. When challenged with a high-fat diet, Atp7bΔIEC mice exhibited profound alterations to fatty acid desaturation and sphingolipid metabolism pathways as well as altered APOB48 distribution in intestinal epithelial cells. Conclusion: Coordinated changes of gut microbiome and lipidome analyses underlie systemic metabolic manifestations in murine WD. Intestine-specific ATP7B deficiency affected both intestinal and systemic response to a high-fat challenge. WD is a systemic disease in which intestinal-specific ATP7B loss and diet influence phenotypic presentations. Keywords: Wilson disease; copper; gut microbiota; lipid metabolism

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“…Lipid metabolism is dysregulated in response to either Cu overload [ 51 – 54 ] or Cu deficiency as observed in Menkes disease [ 55 ]. Our data illustrate that Atp7b activity is required for formation of phosphatidylethanolamine in the developing mice brain.…”

Section: Discussionmentioning

confidence: 99%

Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain

Washington-Hughes

Roy²,

Seneviratne³

et al. 2023

PLoS Genet

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Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl’ cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.

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Lipid and energy metabolism in Wilson disease

Cited by 19 publications

References 151 publications

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

The role of intestine in metabolic dysregulation in murine Wilson disease

Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain

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