Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid Homeostasis
Mutations in ABCC6, an ATP-binding cassette transporter with a so far unknown substrate mainly expressed in the liver and kidney, cause pseudoxanthoma elasticum (PXE). Symptoms of PXE in patients originate from the calcification of elastic fibers in the skin, eye, and vessels. Previous studies sugge...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/9218 |
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| author | Ricarda Plümers Michel R. Osterhage Christopher Lindenkamp Cornelius Knabbe Doris Hendig |
| author_facet | Ricarda Plümers Michel R. Osterhage Christopher Lindenkamp Cornelius Knabbe Doris Hendig |
| author_sort | Ricarda Plümers |
| collection | DOAJ |
| description | Mutations in ABCC6, an ATP-binding cassette transporter with a so far unknown substrate mainly expressed in the liver and kidney, cause pseudoxanthoma elasticum (PXE). Symptoms of PXE in patients originate from the calcification of elastic fibers in the skin, eye, and vessels. Previous studies suggested an involvement of ABCC6 in cholesterol and lipid homeostasis. The intention of this study was to examine the influence of ABCC6 deficiency during adipogenic differentiation of human bone marrow-derived stem cells (hMSCs). Induction of adipogenic differentiation goes along with significantly elevated <i>ABCC6</i> gene expression in mature adipocytes. We generated an <i>ABCC6</i>-deficient cell culture model using clustered regulatory interspaced short palindromic repeat Cas9 (CRISPR–Cas9) system to clarify the role of ABCC6 in lipid homeostasis. The lack of ABCC6 in hMSCs does not influence gene expression of differentiation markers in adipogenesis but results in a decreased triglyceride content in cell culture medium. Protein and gene expression analysis of mature <i>ABCC6</i>-deficient adipocytes showed diminished intra- and extra-cellular lipolysis, release of lipids, and fatty acid neogenesis. Therefore, our results demonstrate impaired lipid trafficking in adipocytes due to <i>ABCC6</i> deficiency, highlighting adipose tissue and peripheral lipid metabolism as a relevant target for uncovering systemic PXE pathogenesis. |
| first_indexed | 2024-03-09T09:55:02Z |
| format | Article |
| id | doaj.art-161a96e05d234a049b84b7152d65317e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T09:55:02Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-161a96e05d234a049b84b7152d65317e2023-12-01T23:47:54ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316921810.3390/ijms23169218Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid HomeostasisRicarda Plümers0Michel R. Osterhage1Christopher Lindenkamp2Cornelius Knabbe3Doris Hendig4Herz- und Diabeteszentrum Nordrhein-Westfalen, Institut für Laboratoriums- und Transfusionsmedizin, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyHerz- und Diabeteszentrum Nordrhein-Westfalen, Institut für Laboratoriums- und Transfusionsmedizin, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyHerz- und Diabeteszentrum Nordrhein-Westfalen, Institut für Laboratoriums- und Transfusionsmedizin, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyHerz- und Diabeteszentrum Nordrhein-Westfalen, Institut für Laboratoriums- und Transfusionsmedizin, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyHerz- und Diabeteszentrum Nordrhein-Westfalen, Institut für Laboratoriums- und Transfusionsmedizin, Universitätsklinik der Ruhr-Universität Bochum, 32545 Bad Oeynhausen, GermanyMutations in ABCC6, an ATP-binding cassette transporter with a so far unknown substrate mainly expressed in the liver and kidney, cause pseudoxanthoma elasticum (PXE). Symptoms of PXE in patients originate from the calcification of elastic fibers in the skin, eye, and vessels. Previous studies suggested an involvement of ABCC6 in cholesterol and lipid homeostasis. The intention of this study was to examine the influence of ABCC6 deficiency during adipogenic differentiation of human bone marrow-derived stem cells (hMSCs). Induction of adipogenic differentiation goes along with significantly elevated <i>ABCC6</i> gene expression in mature adipocytes. We generated an <i>ABCC6</i>-deficient cell culture model using clustered regulatory interspaced short palindromic repeat Cas9 (CRISPR–Cas9) system to clarify the role of ABCC6 in lipid homeostasis. The lack of ABCC6 in hMSCs does not influence gene expression of differentiation markers in adipogenesis but results in a decreased triglyceride content in cell culture medium. Protein and gene expression analysis of mature <i>ABCC6</i>-deficient adipocytes showed diminished intra- and extra-cellular lipolysis, release of lipids, and fatty acid neogenesis. Therefore, our results demonstrate impaired lipid trafficking in adipocytes due to <i>ABCC6</i> deficiency, highlighting adipose tissue and peripheral lipid metabolism as a relevant target for uncovering systemic PXE pathogenesis.https://www.mdpi.com/1422-0067/23/16/9218ABCC6adipogenesislipid homeostasismesenchymal stem cellsmetabolic diseasepseudoxanthoma elasticum |
| spellingShingle | Ricarda Plümers Michel R. Osterhage Christopher Lindenkamp Cornelius Knabbe Doris Hendig Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid Homeostasis International Journal of Molecular Sciences ABCC6 adipogenesis lipid homeostasis mesenchymal stem cells metabolic disease pseudoxanthoma elasticum |
| title | Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid Homeostasis |
| title_full | Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid Homeostasis |
| title_fullStr | Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid Homeostasis |
| title_full_unstemmed | Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid Homeostasis |
| title_short | Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid Homeostasis |
| title_sort | targeting abcc6 in mesenchymal stem cells impairment of mature adipocyte lipid homeostasis |
| topic | ABCC6 adipogenesis lipid homeostasis mesenchymal stem cells metabolic disease pseudoxanthoma elasticum |
| url | https://www.mdpi.com/1422-0067/23/16/9218 |
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