Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles
Abstract Hyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections. We present a new evidence for the mechanism of hyperlipidemic hypersensitivity to microbial inflammation caused by pathogen-derived inducer, LPS. We demons...
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| Format: | Article |
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Nature Portfolio
2021-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-91395-w |
| _version_ | 1818424530788417536 |
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| author | Yan Liu Jozef Zienkiewicz Kelli L. Boyd Taylor E. Smith Zhi-Qi Xu Jacek Hawiger |
| author_facet | Yan Liu Jozef Zienkiewicz Kelli L. Boyd Taylor E. Smith Zhi-Qi Xu Jacek Hawiger |
| author_sort | Yan Liu |
| collection | DOAJ |
| description | Abstract Hyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections. We present a new evidence for the mechanism of hyperlipidemic hypersensitivity to microbial inflammation caused by pathogen-derived inducer, LPS. We demonstrate that hyperlipidemic animals succumbed to a non-lethal dose of LPS whereas normolipidemic controls survived. Strikingly, survival of hyperlipidemic animals was restored when the nuclear import of stress-responsive transcription factors (SRTFs), Sterol Regulatory Element-Binding Proteins (SREBPs), and Carbohydrate-Responsive Element-Binding Proteins (ChREBPs) was impeded by targeting the nuclear transport checkpoint with cell-penetrating, biselective nuclear transport modifier (NTM) peptide. Furthermore, the burst of proinflammatory cytokines and chemokines, microvascular endothelial injury in the liver, lungs, heart, and kidneys, and trafficking of inflammatory cells were also suppressed. To dissect the role of nuclear transport signaling pathways we designed and developed importin-selective NTM peptides. Selective targeting of the importin α5, ferrying SRTFs and ChREBPs, protected 70–100% hyperlipidemic animals. Targeting importin β1, that transports SREBPs, was only effective after 3-week treatment that lowered blood triglycerides, cholesterol, glucose, and averted fatty liver. Thus, the mechanism of hyperlipidemic hypersensitivity to lethal microbial inflammation depends on metabolic and proinflammatory transcription factors mobilization, which can be counteracted by targeting the nuclear transport checkpoint. |
| first_indexed | 2024-12-14T13:59:31Z |
| format | Article |
| id | doaj.art-5a9a67ba778d477782a1456528d9f96b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T13:59:31Z |
| publishDate | 2021-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-5a9a67ba778d477782a1456528d9f96b2022-12-21T22:58:44ZengNature PortfolioScientific Reports2045-23222021-06-0111111710.1038/s41598-021-91395-wHyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttlesYan Liu0Jozef Zienkiewicz1Kelli L. Boyd2Taylor E. Smith3Zhi-Qi Xu4Jacek Hawiger5Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of MedicineDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of MedicineDepartment of Pathology, Microbiology and Immunology, Vanderbilt University School of MedicineDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of MedicineDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of MedicineDivision of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of MedicineAbstract Hyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections. We present a new evidence for the mechanism of hyperlipidemic hypersensitivity to microbial inflammation caused by pathogen-derived inducer, LPS. We demonstrate that hyperlipidemic animals succumbed to a non-lethal dose of LPS whereas normolipidemic controls survived. Strikingly, survival of hyperlipidemic animals was restored when the nuclear import of stress-responsive transcription factors (SRTFs), Sterol Regulatory Element-Binding Proteins (SREBPs), and Carbohydrate-Responsive Element-Binding Proteins (ChREBPs) was impeded by targeting the nuclear transport checkpoint with cell-penetrating, biselective nuclear transport modifier (NTM) peptide. Furthermore, the burst of proinflammatory cytokines and chemokines, microvascular endothelial injury in the liver, lungs, heart, and kidneys, and trafficking of inflammatory cells were also suppressed. To dissect the role of nuclear transport signaling pathways we designed and developed importin-selective NTM peptides. Selective targeting of the importin α5, ferrying SRTFs and ChREBPs, protected 70–100% hyperlipidemic animals. Targeting importin β1, that transports SREBPs, was only effective after 3-week treatment that lowered blood triglycerides, cholesterol, glucose, and averted fatty liver. Thus, the mechanism of hyperlipidemic hypersensitivity to lethal microbial inflammation depends on metabolic and proinflammatory transcription factors mobilization, which can be counteracted by targeting the nuclear transport checkpoint.https://doi.org/10.1038/s41598-021-91395-w |
| spellingShingle | Yan Liu Jozef Zienkiewicz Kelli L. Boyd Taylor E. Smith Zhi-Qi Xu Jacek Hawiger Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles Scientific Reports |
| title | Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles |
| title_full | Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles |
| title_fullStr | Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles |
| title_full_unstemmed | Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles |
| title_short | Hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles |
| title_sort | hyperlipidemic hypersensitivity to lethal microbial inflammation and its reversal by selective targeting of nuclear transport shuttles |
| url | https://doi.org/10.1038/s41598-021-91395-w |
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