Large-Scaled Metabolic Profiling of Human Dermal Fibroblasts Derived from Pseudoxanthoma Elasticum Patients and Healthy Controls

Kuzaj, Patricia; Kühn, Joachim; Michalek, Ryan D.; Karoly, Edward D.; Faust, Isabel; Dabisch-Ruthe, Mareike; Knabbe, Cornelius; Hendig, Doris

doi:10.1371/journal.pone.0108336

Cited by 24 publications

(22 citation statements)

References 72 publications

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“…Up-regulation of Abcd2 mRNA expression in Abcc6 −/− mice might accompany induced ß-oxidation. We have previously shown increased fatty acid oxidation in skin fibroblasts derived from PXE patients [24].…”

Section: Discussionmentioning

confidence: 99%

Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues

et al. 2019

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BackgroundATP-binding cassette (ABC) transporters are involved in a huge range of physiological processes. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum, a metabolic disease with progressive soft tissue calcification.MethodsThe aim of the present study was to analyze gene expression levels of selected ABC transporters associated with cholesterol homeostasis in metabolic active tissues, such as the liver, kidney and white adipose tissue (WAT) of Abcc6−/− mice from an early and late disease stage (six-month-old and 12-month-old mice).ResultsThe strongest regulation of ABC transporter genes was observed in the liver tissue of six-month-old Abcc6−/− mice. Here, we found a significant increase of mRNA expression levels of phospholipid, bile salt and cholesterol/sterol transporters Abcb1b, Abcb11, Abcg1, Abcg5 and Abcg8. Abcd2 mRNA expression was increased by 3.2-fold in the liver tissue. We observed strong upregulation of Abca3 and Abca1 mRNA expression up to 3.3-fold in kidney and WAT, and a 2-fold increase of Abca9 mRNA in the WAT of six-month-old Abcc6 knockout mice. Gene expression levels of Abcb1b and Abcg1 remained increased in the liver tissue after an age-related disease progression, while we observed lower mRNA expression of Abca3 and Abca9 in the kidney and WAT of 12-month-old Abcc6−/− mice.ConclusionsThese data support previous findings that Abcc6 deficiency leads to an altered gene expression of other ABC transporters depending on the status of disease progression. The increased expression of fatty acid, bile salt and cholesterol/sterol transporters may be linked to an altered cholesterol and lipoprotein metabolism due to a loss of Abcc6 function.Electronic supplementary materialThe online version of this article (10.1186/s12944-018-0943-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues

et al. 2019

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“…Most of the differentially expressed proteins were related to metabolic enzymes (e.g., pyruvate kinase, acetyl-CoA acetyltransferase, acyl-CoA dehydrogenase, 3hydroxyisobutyrate dehydrogenase, peptidyl-prolyl cis-trans isomerase B), indicating that mitochondria can contribute to PXE metabolic changes (Kuzaj et al, 2014).…”

Section: Shotgun Proteomics Analysis Reveals Changes In Mitochondrialmentioning

confidence: 99%

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Lofaro

Boraldi

García-Fernández

et al. 2020

Front. Cell Dev. Biol.

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Pseudoxanthoma elasticum (PXE) is a genetic disease considered as a paradigm of ectopic mineralization disorders, being characterized by multisystem clinical manifestations due to progressive calcification of skin, eyes, and the cardiovascular system, resembling an age-related phenotype. Although fibroblasts do not express the pathogenic ABCC6 gene, nevertheless these cells are still under investigation because they regulate connective tissue homeostasis, generating the “arena” where cells and extracellular matrix components can promote pathologic calcification and where activation of pro-osteogenic factors can be associated to pathways involving mitochondrial metabolism. The aim of the present study was to integrate structural and bioenergenetic features to deeply investigate mitochondria from control and from PXE fibroblasts cultured in standard conditions and to explore the role of mitochondria in the development of the PXE fibroblasts’ pathologic phenotype. Proteomic, biochemical, and morphological data provide new evidence that in basal culture conditions (1) the protein profile of PXE mitochondria reveals a number of differentially expressed proteins, suggesting changes in redox balance, oxidative phosphorylation, and calcium homeostasis in addition to modified structure and organization, (2) measure of oxygen consumption indicates that the PXE mitochondria have a low ability to cope with a sudden increased need for ATP via oxidative phosphorylation, (3) mitochondrial membranes are highly polarized in PXE fibroblasts, and this condition contributes to increased reactive oxygen species levels, (4) ultrastructural alterations in PXE mitochondria are associated with functional changes, and (5) PXE fibroblasts exhibit a more abundant, branched, and interconnected mitochondrial network compared to control cells, indicating that fusion prevail over fission events. In summary, the present study demonstrates that mitochondria are modified in PXE fibroblasts. Since mitochondria are key players in the development of the aging process, fibroblasts cultured from aged individuals or aged in vitro are more prone to calcify, and in PXE, calcified tissues remind features of premature aging syndromes; it can be hypothesized that mitochondria represent a common link contributing to the development of ectopic calcification in aging and in diseases. Therefore, ameliorating mitochondrial functions and cell metabolism could open new strategies to positively regulate a number of signaling pathways associated to pathologic calcification.

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“…Two main hypotheses can be considered. Firstly, the cell-based hypothesis holds that a lack of functional ABCC6 protein at peripheral sites leads to ectopic mineralization [ 66 ]. Although cultured fibroblasts taken from PXE patients’ dermis display biochemical and genetic abnormalities [ 66 , 67 ], the cell-based hypothesis is weakened by the fact that ABCC6 mRNA is expressed at only low to moderate levels in tissues outside the liver in healthy controls [ 47 ] [ 68 ].…”

Section: Etiologymentioning

confidence: 99%

Pseudoxanthoma elasticum

Germain

2017

Orphanet J Rare Dis

144

147

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Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch’s membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

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Large-Scaled Metabolic Profiling of Human Dermal Fibroblasts Derived from Pseudoxanthoma Elasticum Patients and Healthy Controls

Cited by 24 publications

References 72 publications

Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues

Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Pseudoxanthoma elasticum

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