ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

Kuzaj, Patricia; Kühn, Joachim; Dabisch-Ruthe, Mareike; Faust, Isabel; Götting, Christian; Knabbe, Cornelius; Hendig, Doris

doi:10.1186/1476-511x-13-118

Cited by 33 publications

(50 citation statements)

References 78 publications

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“…On the other hand, serum deprivation should lead to an endogenous synthesis and accumulation of newly synthesized metabolites in ABCC6 deficient PXE fibroblasts which might also be possible substrates of ABCC6. Furthermore, newly published data showed significantly induced ABCC6 mRNA expression under serum starvation, relative to standard cultivation in 10% FCS [23] .…”

Section: Discussionmentioning

confidence: 94%

“…Serum starvation was further conducted to induce oxidative stress conditions in human dermal fibroblasts [21] , as well as to enhance metabolic and proteolytic activity in these cells [22] , to closely mimic the described cellular phenotype of PXE. Additionally, serum withdrawal was shown to induce ABCC6 mRNA expression significantly, compared to standard cultivation method in 10% FCS [23] .…”

Section: Introductionmentioning

confidence: 91%

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

et al. 2014

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Mutations in the ABC transporter ABCC6 were recently identified as cause of Pseudoxanthoma elasticum (PXE), a rare genetic disorder characterized by progressive mineralization of elastic fibers. We used an untargeted metabolic approach to identify biochemical differences between human dermal fibroblasts from healthy controls and PXE patients in an attempt to find a link between ABCC6 deficiency, cellular metabolic alterations and disease pathogenesis. 358 compounds were identified by mass spectrometry covering lipids, amino acids, peptides, carbohydrates, nucleotides, vitamins and cofactors, xenobiotics and energy metabolites. We found substantial differences in glycerophospholipid composition, leucine dipeptides, and polypeptides as well as alterations in pantothenate and guanine metabolism to be significantly associated with PXE pathogenesis. These findings can be linked to extracellular matrix remodeling and increased oxidative stress, which reflect characteristic hallmarks of PXE. Our study could facilitate a better understanding of biochemical pathways involved in soft tissue mineralization.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 91%

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

et al. 2014

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“…Furthermore, MMP2 was found to be upregulated in PXE fibroblasts; MGP was found to be highly uncarboxylated and thus inactive to counteract soft tissue mineralization; multiple pro-osteogenic pathways, that is, the BMP2-Smad-RUNX2 (BMP2: bone morphogenetic protein 2, OMIM ∗ 112261; Smad: mothers against decapentaplegic, Drosophila , homolog of, OMIM ∗ 601366; RUNX2: runt-related transcription factor 2, OMIM ∗ 60021) and TGF β 2-Smad2/3 WNT pathways (TGF β 2: transforming growth factor, β 2, OMIM ∗ 190220) and the MSX2-canonical WNT (MSX2: muscle segment homeobox, Drosophila , homolog of, 2, OMIM ∗ 123101; canonical WNT: wingless-type MMTV integration site family, OMIM ∗ 164820), were found to be upregulated in fibroblasts from PXE patients and were associated with an abnormal cholesterol and lipoprotein metabolism, reinforcing the higher cardiovascular risk found in PXE patients [ 15 , 25 , 81 , 82 ]. Very recently, Dabisch-Ruthe et al identified a strong reduction of the inorganic pyrophosphate (PPi) levels in dermal PXE fibroblasts leading to ectopic mineralization.…”

Section: A Network Approach Towards a Better Understanding Of The mentioning

confidence: 97%

“…This fed the hypothesis of PXE as a metabolic disease, in which the defective ABCC6 transporter is unable to secrete one or more substrates into the serum. More recently, knowledge on mediators involved in ABCC6-related mineralization was derived from dermal PXE fibroblasts, using metabolomics and proteomics technologies (see below) and expression arrays [ 46 , 80 , 81 ].…”

Section: A Network Approach Towards a Better Understanding Of The mentioning

confidence: 99%

“…Furthermore, the serum also contained elevated PCSK9 (proprotein convertase, subtilisin/kexin-type 9, OMIM ∗ 607786) levels, which cause a decrease of (extra)hepatic levels of LDL-C (low-density lipoprotein cholesterol) receptors and an increase in LDL plasma concentration. In PXE fibroblasts a reduction of ApoE mRNA expression was identified [ 81 ]. These findings further stress the importance of ABCC6 variants, both gain- and loss-of-function, in the cardiovascular disease risk of the general population.…”

Section: Relevance Of Abcc6 For Complex and Rare Disorders And Dismentioning

confidence: 99%

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The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders

Vilder

Vanakker

2015

BioMed Research International

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The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders. Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology. ABCC6, the gene responsible for pseudoxanthoma elasticum, an autosomal recessive ectopic mineralization disorder, can be considered a paradigm gene with relevance that reaches far beyond this enigmatic orphan disease. Indeed, common traits such as chronic kidney disease or cardiovascular disorders have been linked to the ABCC6 gene. While during the last decade the awareness of the wide ramifications of ABCC6 has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them. To gain more insights, multiple approaches are being used including next-generation sequencing, computational methods, and various “omics” technologies. Much effort is made to place the vast amount of data that is gathered in an integrated system-biological network; the involvement of ABCC6 in common disorders provides a good view on the wide implications and potential of such a network. In this review, we summarize the network approaches used to study ABCC6 and the role of this gene in several complex diseases.

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From membrane to mineralization: the curious case of the ABCC6 transporter

et al. 2020

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ATP‐binding cassette subfamily C member 6 gene/protein (ABCC6) is an ATP‐dependent transmembrane transporter predominantly expressed in the liver and the kidney. ABCC6 first came to attention in human medicine when it was discovered in 2000 that mutations in its encoding gene, ABCC6, caused the autosomal recessive multisystemic mineralization disease pseudoxanthoma elasticum (PXE). Since then, the physiological and pathological roles of ABCC6 have been the subject of intense research. In the last 20 years, significant findings have clarified ABCC6 structure as well as its physiological role in mineralization homeostasis in humans and animal models. Yet, several facets of ABCC6 biology remain currently incompletely understood, ranging from the precise nature of its substrate(s) to the increasingly complex molecular genetics. Nonetheless, advances in our understanding of pathophysiological mechanisms causing mineralization lead to several treatment options being suggested or already tested in pilot clinical trials for ABCC6 deficiency. This review highlights current knowledge of ABCC6 and the challenges ahead, particularly the attempts to translate basic science into clinical practice.

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ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

Cited by 33 publications

References 78 publications

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

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

The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders

From membrane to mineralization: the curious case of the ABCC6 transporter

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