Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes
Type 2 diabetes mellitus is a chronic metabolic disease with no cure. Adipose tissue is a major site of systemic insulin resistance. Sortilin is a central component of the glucose transporter -Glut4 storage vesicles (GSV) which translocate to the plasma membrane to uptake glucose from circulation. H...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/18/14324 |
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| author | Ashley Lui Rekha S. Patel Meredith Krause-Hauch Robert P. Sparks Niketa A. Patel |
| author_facet | Ashley Lui Rekha S. Patel Meredith Krause-Hauch Robert P. Sparks Niketa A. Patel |
| author_sort | Ashley Lui |
| collection | DOAJ |
| description | Type 2 diabetes mellitus is a chronic metabolic disease with no cure. Adipose tissue is a major site of systemic insulin resistance. Sortilin is a central component of the glucose transporter -Glut4 storage vesicles (GSV) which translocate to the plasma membrane to uptake glucose from circulation. Here, using human adipocytes we demonstrate the presence of the alternatively spliced, truncated sortilin variant (Sort_T) whose expression is significantly increased in diabetic adipose tissue. Artificial-intelligence-based modeling, molecular dynamics, intrinsically disordered region analysis, and co-immunoprecipitation demonstrated association of Sort_T with Glut4 and decreased glucose uptake in adipocytes. The results show that glucagon-like peptide-1 (GLP1) hormone decreases Sort_T. We deciphered the molecular mechanism underlying GLP1 regulation of alternative splicing of human sortilin. Using splicing minigenes and RNA-immunoprecipitation assays, the results show that GLP1 regulates Sort_T alternative splicing via the splice factor, TRA2B. We demonstrate that targeted antisense oligonucleotide morpholinos reduces Sort_T levels and improves glucose uptake in diabetic adipocytes. Thus, we demonstrate that GLP1 regulates alternative splicing of sortilin in human diabetic adipocytes. |
| first_indexed | 2024-03-10T22:39:04Z |
| format | Article |
| id | doaj.art-43c51aa5df7f4dec89b060e1c10f589d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T22:39:04Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-43c51aa5df7f4dec89b060e1c10f589d2023-11-19T11:11:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124181432410.3390/ijms241814324Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in AdipocytesAshley Lui0Rekha S. Patel1Meredith Krause-Hauch2Robert P. Sparks3Niketa A. Patel4Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USAResearch Service, James A. Haley Veterans Hospital, Tampa, FL 33612, USADepartment of Molecular Medicine, University of South Florida, Tampa, FL 33612, USAResearch Service, James A. Haley Veterans Hospital, Tampa, FL 33612, USADepartment of Molecular Medicine, University of South Florida, Tampa, FL 33612, USAType 2 diabetes mellitus is a chronic metabolic disease with no cure. Adipose tissue is a major site of systemic insulin resistance. Sortilin is a central component of the glucose transporter -Glut4 storage vesicles (GSV) which translocate to the plasma membrane to uptake glucose from circulation. Here, using human adipocytes we demonstrate the presence of the alternatively spliced, truncated sortilin variant (Sort_T) whose expression is significantly increased in diabetic adipose tissue. Artificial-intelligence-based modeling, molecular dynamics, intrinsically disordered region analysis, and co-immunoprecipitation demonstrated association of Sort_T with Glut4 and decreased glucose uptake in adipocytes. The results show that glucagon-like peptide-1 (GLP1) hormone decreases Sort_T. We deciphered the molecular mechanism underlying GLP1 regulation of alternative splicing of human sortilin. Using splicing minigenes and RNA-immunoprecipitation assays, the results show that GLP1 regulates Sort_T alternative splicing via the splice factor, TRA2B. We demonstrate that targeted antisense oligonucleotide morpholinos reduces Sort_T levels and improves glucose uptake in diabetic adipocytes. Thus, we demonstrate that GLP1 regulates alternative splicing of sortilin in human diabetic adipocytes.https://www.mdpi.com/1422-0067/24/18/14324type 2 diabeteshuman adipocyteshuman adipose tissueglucose uptakesplicing minigeneantisense oligonucleotides |
| spellingShingle | Ashley Lui Rekha S. Patel Meredith Krause-Hauch Robert P. Sparks Niketa A. Patel Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes International Journal of Molecular Sciences type 2 diabetes human adipocytes human adipose tissue glucose uptake splicing minigene antisense oligonucleotides |
| title | Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes |
| title_full | Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes |
| title_fullStr | Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes |
| title_full_unstemmed | Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes |
| title_short | Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes |
| title_sort | regulation of human sortilin alternative splicing by glucagon like peptide 1 glp1 in adipocytes |
| topic | type 2 diabetes human adipocytes human adipose tissue glucose uptake splicing minigene antisense oligonucleotides |
| url | https://www.mdpi.com/1422-0067/24/18/14324 |
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