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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...

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Autores principales: He, Huijun, Zhong, Yu, Wang, Honglian, Tang, Patrick Ming-Kuen, Xue, Vivian Weiwen, Chen, Xiaocui, Chen, Jiaoyi, Huang, Xiaoru, Wang, Cheng, Lan, Huiyao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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