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Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ
Transforming growth factor-β (TGF-β)/Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases. However, the role of Smad3 in dyslipidemia and non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes remains unclear, and whether targeting Smad3 has a therapeuti...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380492/ https://www.ncbi.nlm.nih.gov/pubmed/37511155 http://dx.doi.org/10.3390/ijms241411396 |
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author | He, Huijun Zhong, Yu Wang, Honglian Tang, Patrick Ming-Kuen Xue, Vivian Weiwen Chen, Xiaocui Chen, Jiaoyi Huang, Xiaoru Wang, Cheng Lan, Huiyao |
author_facet | He, Huijun Zhong, Yu Wang, Honglian Tang, Patrick Ming-Kuen Xue, Vivian Weiwen Chen, Xiaocui Chen, Jiaoyi Huang, Xiaoru Wang, Cheng Lan, Huiyao |
author_sort | He, Huijun |
collection | PubMed |
description | Transforming growth factor-β (TGF-β)/Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases. However, the role of Smad3 in dyslipidemia and non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes remains unclear, and whether targeting Smad3 has a therapeutic effect on these metabolic abnormalities remains unexplored. These topics were investigated in this study in Smad3 knockout (KO)-db/db mice and by treating db/db mice with a Smad3-specific inhibitor SIS3. Compared to Smad3 wild-type (WT)-db/db mice, Smad3 KO-db/db mice were protected against dyslipidemia and NAFLD. Similarly, treatment of db/db mice with SIS3 at week 4 before the onset of type 2 diabetes until week 12 was capable of lowering blood glucose levels and improving diabetic dyslipidemia and NAFLD. In addition, using RNA-sequencing, the potential Smad3-target genes related to lipid metabolism was identified in the liver tissues of Smad3 KO/WT mice, and the regulatory mechanisms were investigated. Mechanistically, we uncovered that Smad3 targeted peroxisome proliferator-activated receptor delta (PPARδ) to induce dyslipidemia and NAFLD in db/db mice, which was improved by genetically deleting and pharmacologically inhibiting Smad3. |
format | Online Article Text |
id | pubmed-10380492 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-103804922023-07-29 Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ He, Huijun Zhong, Yu Wang, Honglian Tang, Patrick Ming-Kuen Xue, Vivian Weiwen Chen, Xiaocui Chen, Jiaoyi Huang, Xiaoru Wang, Cheng Lan, Huiyao Int J Mol Sci Article Transforming growth factor-β (TGF-β)/Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases. However, the role of Smad3 in dyslipidemia and non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes remains unclear, and whether targeting Smad3 has a therapeutic effect on these metabolic abnormalities remains unexplored. These topics were investigated in this study in Smad3 knockout (KO)-db/db mice and by treating db/db mice with a Smad3-specific inhibitor SIS3. Compared to Smad3 wild-type (WT)-db/db mice, Smad3 KO-db/db mice were protected against dyslipidemia and NAFLD. Similarly, treatment of db/db mice with SIS3 at week 4 before the onset of type 2 diabetes until week 12 was capable of lowering blood glucose levels and improving diabetic dyslipidemia and NAFLD. In addition, using RNA-sequencing, the potential Smad3-target genes related to lipid metabolism was identified in the liver tissues of Smad3 KO/WT mice, and the regulatory mechanisms were investigated. Mechanistically, we uncovered that Smad3 targeted peroxisome proliferator-activated receptor delta (PPARδ) to induce dyslipidemia and NAFLD in db/db mice, which was improved by genetically deleting and pharmacologically inhibiting Smad3. MDPI 2023-07-13 /pmc/articles/PMC10380492/ /pubmed/37511155 http://dx.doi.org/10.3390/ijms241411396 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article He, Huijun Zhong, Yu Wang, Honglian Tang, Patrick Ming-Kuen Xue, Vivian Weiwen Chen, Xiaocui Chen, Jiaoyi Huang, Xiaoru Wang, Cheng Lan, Huiyao Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ |
title | Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ |
title_full | Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ |
title_fullStr | Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ |
title_full_unstemmed | Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ |
title_short | Smad3 Mediates Diabetic Dyslipidemia and Fatty Liver in db/db Mice by Targeting PPARδ |
title_sort | smad3 mediates diabetic dyslipidemia and fatty liver in db/db mice by targeting pparδ |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10380492/ https://www.ncbi.nlm.nih.gov/pubmed/37511155 http://dx.doi.org/10.3390/ijms241411396 |
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