Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice
ObjectiveThis study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.Methodsdb/db diabetic mice were administered PAItrap3 (5.7 mg/kg/day, IV) for 21 consecutive days, and its impact on metabolic, gene expression, and...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1596655/full |
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| author | Linxi Wang Zhouyangyang Zhang Menghua Lin Liqin Qi Libin Liu Zhuo Chen Shuzhi Tang Lijing Wang |
| author_facet | Linxi Wang Zhouyangyang Zhang Menghua Lin Liqin Qi Libin Liu Zhuo Chen Shuzhi Tang Lijing Wang |
| author_sort | Linxi Wang |
| collection | DOAJ |
| description | ObjectiveThis study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.Methodsdb/db diabetic mice were administered PAItrap3 (5.7 mg/kg/day, IV) for 21 consecutive days, and its impact on metabolic, gene expression, and lipidomic profiles was assessed. Western blot analysis was performed to examine lipid metabolism-related proteins in white adipose tissue (FASN, HSL, CPT1A, ACADM) and autophagy markers (LC3B, P62, Parkin, PGC1α, PPARGC1B). Additionally, RNA-seq and targeted lipidomics were employed to analyze gene expression and lipid metabolic alterations.ResultsPAItrap3 significantly reduced blood glucose and glycated hemoglobin levels while improving insulin sensitivity. In lipid metabolism, FASN and HSL levels were upregulated, whereas CPT1A and ACADM levels were downregulated in the DMP group. Regarding the autophagy pathway, PPARGC1B, LC3B, and PGC1α expression levels were increased, while P62 and Parkin levels were decreased. Lipidomics analysis revealed that triglycerides (TG) and diacylglycerols (DG) were generally downregulated, with TG (18:2/18:2/18:2) (0.96 [0.8491, 1]), LPI (18:0) (0.96 [0.8491, 1]), and MLCL (14:3/20:4/22:6) (0.96 [0.8491, 1]) identified as key metabolites.ConclusionThis study finds that PAItrap3 modulates lipid metabolism, energy homeostasis, and autophagy pathways, thereby improving metabolic dysfunction in diabetic mice. These findings highlight its potential therapeutic value for treating diabetes-associated lipid metabolic disorders. |
| format | Article |
| id | doaj-art-ec30ba5ae67942df9f6e28d9e94e59a7 |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-ec30ba5ae67942df9f6e28d9e94e59a72025-08-20T02:23:46ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-06-011610.3389/fphar.2025.15966551596655Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db miceLinxi Wang0Zhouyangyang Zhang1Menghua Lin2Liqin Qi3Libin Liu4Zhuo Chen5Shuzhi Tang6Lijing Wang7Department of Endocrinology and Metabolism, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, ChinaDepartment of Endocrinology and Metabolism, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, ChinaDepartment of Endocrinology and Metabolism, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, ChinaDepartment of Endocrinology and Metabolism, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, ChinaDepartment of Endocrinology and Metabolism, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, ChinaState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian College, University of Chinese Academy of Sciences, Fuzhou, ChinaFujian Provincial Key Laboratory of Ecology Toxicological Effects and Control for Emerging Contaminants, Key Laboratory of Ecological Environment and Information Atlas, Fujian Provincial University, College of Environmental and Biological Engineering, Putian University, Putian, Fujian, ChinaDepartment of Endocrinology and Metabolism, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou, ChinaObjectiveThis study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.Methodsdb/db diabetic mice were administered PAItrap3 (5.7 mg/kg/day, IV) for 21 consecutive days, and its impact on metabolic, gene expression, and lipidomic profiles was assessed. Western blot analysis was performed to examine lipid metabolism-related proteins in white adipose tissue (FASN, HSL, CPT1A, ACADM) and autophagy markers (LC3B, P62, Parkin, PGC1α, PPARGC1B). Additionally, RNA-seq and targeted lipidomics were employed to analyze gene expression and lipid metabolic alterations.ResultsPAItrap3 significantly reduced blood glucose and glycated hemoglobin levels while improving insulin sensitivity. In lipid metabolism, FASN and HSL levels were upregulated, whereas CPT1A and ACADM levels were downregulated in the DMP group. Regarding the autophagy pathway, PPARGC1B, LC3B, and PGC1α expression levels were increased, while P62 and Parkin levels were decreased. Lipidomics analysis revealed that triglycerides (TG) and diacylglycerols (DG) were generally downregulated, with TG (18:2/18:2/18:2) (0.96 [0.8491, 1]), LPI (18:0) (0.96 [0.8491, 1]), and MLCL (14:3/20:4/22:6) (0.96 [0.8491, 1]) identified as key metabolites.ConclusionThis study finds that PAItrap3 modulates lipid metabolism, energy homeostasis, and autophagy pathways, thereby improving metabolic dysfunction in diabetic mice. These findings highlight its potential therapeutic value for treating diabetes-associated lipid metabolic disorders.https://www.frontiersin.org/articles/10.3389/fphar.2025.1596655/fullPAI-1 inhibitorlipid metabolismautophagyenergy metabolismdiabetes mellitus |
| spellingShingle | Linxi Wang Zhouyangyang Zhang Menghua Lin Liqin Qi Libin Liu Zhuo Chen Shuzhi Tang Lijing Wang Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice Frontiers in Pharmacology PAI-1 inhibitor lipid metabolism autophagy energy metabolism diabetes mellitus |
| title | Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice |
| title_full | Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice |
| title_fullStr | Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice |
| title_full_unstemmed | Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice |
| title_short | Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice |
| title_sort | mechanistic insights into the pai 1 inhibitor paitrap3 enhancing lipid metabolism in adipose tissue of diabetic db db mice |
| topic | PAI-1 inhibitor lipid metabolism autophagy energy metabolism diabetes mellitus |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1596655/full |
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