Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells
Metabolic stress, such as lipotoxicity, affects the DNA methylation profile in pancreatic β-cells and thus contributes to β-cell failure and the progression of type 2 diabetes (T2D). Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme that is involved in monounsaturated fatty acid synthesis,...
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MDPI AG
2020-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/18/6844 |
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| author | Aneta M. Dobosz Justyna Janikiewicz Anna M. Borkowska Anna Dziewulska Ewelina Lipiec Pawel Dobrzyn Wojciech M. Kwiatek Agnieszka Dobrzyn |
| author_facet | Aneta M. Dobosz Justyna Janikiewicz Anna M. Borkowska Anna Dziewulska Ewelina Lipiec Pawel Dobrzyn Wojciech M. Kwiatek Agnieszka Dobrzyn |
| author_sort | Aneta M. Dobosz |
| collection | DOAJ |
| description | Metabolic stress, such as lipotoxicity, affects the DNA methylation profile in pancreatic β-cells and thus contributes to β-cell failure and the progression of type 2 diabetes (T2D). Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme that is involved in monounsaturated fatty acid synthesis, which protects pancreatic β-cells against lipotoxicity. The present study found that SCD1 is also required for the establishment and maintenance of DNA methylation patterns in β-cells. We showed that SCD1 inhibition/deficiency caused DNA hypomethylation and changed the methyl group distribution within chromosomes in β-cells. Lower levels of DNA methylation in SCD1-deficient β-cells were followed by lower levels of DNA methyltransferase 1 (DNMT1). We also found that the downregulation of SCD1 in pancreatic β-cells led to the activation of adenosine monophosphate-activated protein kinase (AMPK) and an increase in the activity of the NAD-dependent deacetylase sirtuin-1 (SIRT1). Furthermore, the physical association between DNMT1 and SIRT1 stimulated the deacetylation of DNMT1 under conditions of SCD1 inhibition/downregulation, suggesting a mechanism by which SCD1 exerts control over DNMT1. We also found that SCD1-deficient β-cells that were treated with compound c, an inhibitor of AMPK, were characterized by higher levels of both global DNA methylation and DNMT1 protein expression compared with untreated cells. Therefore, we found that activation of the AMPK/SIRT1 signaling pathway mediates the effect of SCD1 inhibition/deficiency on DNA methylation status in pancreatic β-cells. Altogether, these findings suggest that SCD1 is a gatekeeper that protects β-cells against the lipid-derived loss of DNA methylation and provide mechanistic insights into the mechanism by which SCD1 regulates DNA methylation patterns in β-cells and T2D-relevant tissues. |
| first_indexed | 2024-03-10T16:14:58Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:14:58Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d55a956d7efa4976b5d6ffb3b1da4d8d2023-11-20T14:10:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-09-012118684410.3390/ijms21186844Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-CellsAneta M. Dobosz0Justyna Janikiewicz1Anna M. Borkowska2Anna Dziewulska3Ewelina Lipiec4Pawel Dobrzyn5Wojciech M. Kwiatek6Agnieszka Dobrzyn7Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandLaboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandDivision of Interdisciplinary Research, Institute of Nuclear Physics, Polish Academy of Sciences, 31-342 Krakow, PolandLaboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandDivision of Interdisciplinary Research, Institute of Nuclear Physics, Polish Academy of Sciences, 31-342 Krakow, PolandLaboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandDivision of Interdisciplinary Research, Institute of Nuclear Physics, Polish Academy of Sciences, 31-342 Krakow, PolandLaboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandMetabolic stress, such as lipotoxicity, affects the DNA methylation profile in pancreatic β-cells and thus contributes to β-cell failure and the progression of type 2 diabetes (T2D). Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme that is involved in monounsaturated fatty acid synthesis, which protects pancreatic β-cells against lipotoxicity. The present study found that SCD1 is also required for the establishment and maintenance of DNA methylation patterns in β-cells. We showed that SCD1 inhibition/deficiency caused DNA hypomethylation and changed the methyl group distribution within chromosomes in β-cells. Lower levels of DNA methylation in SCD1-deficient β-cells were followed by lower levels of DNA methyltransferase 1 (DNMT1). We also found that the downregulation of SCD1 in pancreatic β-cells led to the activation of adenosine monophosphate-activated protein kinase (AMPK) and an increase in the activity of the NAD-dependent deacetylase sirtuin-1 (SIRT1). Furthermore, the physical association between DNMT1 and SIRT1 stimulated the deacetylation of DNMT1 under conditions of SCD1 inhibition/downregulation, suggesting a mechanism by which SCD1 exerts control over DNMT1. We also found that SCD1-deficient β-cells that were treated with compound c, an inhibitor of AMPK, were characterized by higher levels of both global DNA methylation and DNMT1 protein expression compared with untreated cells. Therefore, we found that activation of the AMPK/SIRT1 signaling pathway mediates the effect of SCD1 inhibition/deficiency on DNA methylation status in pancreatic β-cells. Altogether, these findings suggest that SCD1 is a gatekeeper that protects β-cells against the lipid-derived loss of DNA methylation and provide mechanistic insights into the mechanism by which SCD1 regulates DNA methylation patterns in β-cells and T2D-relevant tissues.https://www.mdpi.com/1422-0067/21/18/6844SCD1DNA methylationAMPKepigenetic regulationlipotoxicity |
| spellingShingle | Aneta M. Dobosz Justyna Janikiewicz Anna M. Borkowska Anna Dziewulska Ewelina Lipiec Pawel Dobrzyn Wojciech M. Kwiatek Agnieszka Dobrzyn Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells International Journal of Molecular Sciences SCD1 DNA methylation AMPK epigenetic regulation lipotoxicity |
| title | Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells |
| title_full | Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells |
| title_fullStr | Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells |
| title_full_unstemmed | Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells |
| title_short | Stearoyl-CoA Desaturase 1 Activity Determines the Maintenance of DNMT1-Mediated DNA Methylation Patterns in Pancreatic β-Cells |
| title_sort | stearoyl coa desaturase 1 activity determines the maintenance of dnmt1 mediated dna methylation patterns in pancreatic β cells |
| topic | SCD1 DNA methylation AMPK epigenetic regulation lipotoxicity |
| url | https://www.mdpi.com/1422-0067/21/18/6844 |
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