Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice
This study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice. db/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 prof...
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| Published in | Frontiers in pharmacology Vol. 16; p. 1596655 |
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| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
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Frontiers Media S.A
12.06.2025
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| ISSN | 1663-9812 1663-9812 |
| DOI | 10.3389/fphar.2025.1596655 |
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| Abstract | This study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.
db/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.
PAItrap3 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.
This 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. |
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| AbstractList | 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. This study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.ObjectiveThis study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.db/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.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.PAItrap3 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.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.This 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.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. This study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice. db/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. PAItrap3 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. This 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. |
| Author | Wang, Linxi Tang, Shuzhi Chen, Zhuo Lin, Menghua Liu, Libin Zhang, Zhouyangyang Qi, Liqin Wang, Lijing |
| AuthorAffiliation | 1 Department of Endocrinology and Metabolism , Fujian Institute of Endocrinology , Fujian Medical University Union Hospital , Fuzhou , China 3 Fujian 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 , China 2 State 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 , China |
| AuthorAffiliation_xml | – name: 1 Department of Endocrinology and Metabolism , Fujian Institute of Endocrinology , Fujian Medical University Union Hospital , Fuzhou , China – name: 3 Fujian 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 , China – name: 2 State 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 , China |
| Author_xml | – sequence: 1 givenname: Linxi surname: Wang fullname: Wang, Linxi – sequence: 2 givenname: Zhouyangyang surname: Zhang fullname: Zhang, Zhouyangyang – sequence: 3 givenname: Menghua surname: Lin fullname: Lin, Menghua – sequence: 4 givenname: Liqin surname: Qi fullname: Qi, Liqin – sequence: 5 givenname: Libin surname: Liu fullname: Liu, Libin – sequence: 6 givenname: Zhuo surname: Chen fullname: Chen, Zhuo – sequence: 7 givenname: Shuzhi surname: Tang fullname: Tang, Shuzhi – sequence: 8 givenname: Lijing surname: Wang fullname: Wang, Lijing |
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| Keywords | diabetes mellitus autophagy PAI-1 inhibitor energy metabolism lipid metabolism |
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| Snippet | This study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.
db/db diabetic... This study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.ObjectiveThis... ObjectiveThis study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic... |
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| SubjectTerms | autophagy diabetes mellitus energy metabolism lipid metabolism PAI-1 inhibitor Pharmacology |
| Title | Mechanistic insights into the PAI-1 inhibitor PAItrap3: enhancing lipid metabolism in adipose tissue of diabetic db/db mice |
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