Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic Shock
Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Mechanistic investigations into sepsis have mainly focused on targeting inflammatory pathways; however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulati...
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MDPI AG
2022-12-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/24/4080 |
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| author | Jolien Vandewalle Bruno Garcia Steven Timmermans Tineke Vanderhaeghen Lise Van Wyngene Melanie Eggermont Hester Dufoor Céline Van Dender Fëllanza Halimi Siska Croubels Antoine Herpain Claude Libert |
| author_facet | Jolien Vandewalle Bruno Garcia Steven Timmermans Tineke Vanderhaeghen Lise Van Wyngene Melanie Eggermont Hester Dufoor Céline Van Dender Fëllanza Halimi Siska Croubels Antoine Herpain Claude Libert |
| author_sort | Jolien Vandewalle |
| collection | DOAJ |
| description | Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Mechanistic investigations into sepsis have mainly focused on targeting inflammatory pathways; however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulations that take place in sepsis might uncover novel therapeutic opportunities. The role of peroxisome proliferator-activated receptor alpha (PPARɑ) in liver dysfunction during sepsis has recently been described, and restoring PPARɑ signaling has proven to be successful in mouse polymicrobial sepsis. To confirm that such therapy might be translated to septic patients, we analyzed metabolic perturbations in the liver of a porcine fecal peritonitis model. Resuscitation with fluids, vasopressor, antimicrobial therapy and abdominal lavage were applied to the pigs in order to mimic human clinical care. By using RNA-seq, we detected downregulated PPARɑ signaling in the livers of septic pigs and that reduced PPARɑ levels correlated well with disease severity. As PPARɑ regulates the expression of many genes involved in fatty acid oxidation, the reduced expression of these target genes, concomitant with increased free fatty acids in plasma and ectopic lipid deposition in the liver, was observed. The results obtained with pigs are in agreement with earlier observations seen in mice and support the potential of targeting defective PPARɑ signaling in clinical research. |
| first_indexed | 2024-03-09T17:12:54Z |
| format | Article |
| id | doaj.art-f6cf66ff733845afa1be4ac620887e15 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T17:12:54Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-f6cf66ff733845afa1be4ac620887e152023-11-24T13:55:30ZengMDPI AGCells2073-44092022-12-011124408010.3390/cells11244080Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic ShockJolien Vandewalle0Bruno Garcia1Steven Timmermans2Tineke Vanderhaeghen3Lise Van Wyngene4Melanie Eggermont5Hester Dufoor6Céline Van Dender7Fëllanza Halimi8Siska Croubels9Antoine Herpain10Claude Libert11VIB Center for Inflammation Research, VIB, 9052 Ghent, BelgiumExperimental Laboratory of Intensive Care, Université Libre de Bruxelles, 1050 Brussels, BelgiumVIB Center for Inflammation Research, VIB, 9052 Ghent, BelgiumVIB Center for Inflammation Research, VIB, 9052 Ghent, BelgiumVIB Center for Inflammation Research, VIB, 9052 Ghent, BelgiumVIB Center for Inflammation Research, VIB, 9052 Ghent, BelgiumVIB Center for Inflammation Research, VIB, 9052 Ghent, BelgiumVIB Center for Inflammation Research, VIB, 9052 Ghent, BelgiumDepartment of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, BelgiumDepartment of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, BelgiumExperimental Laboratory of Intensive Care, Université Libre de Bruxelles, 1050 Brussels, BelgiumVIB Center for Inflammation Research, VIB, 9052 Ghent, BelgiumDespite decades of research, sepsis remains one of the most urgent unmet medical needs. Mechanistic investigations into sepsis have mainly focused on targeting inflammatory pathways; however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulations that take place in sepsis might uncover novel therapeutic opportunities. The role of peroxisome proliferator-activated receptor alpha (PPARɑ) in liver dysfunction during sepsis has recently been described, and restoring PPARɑ signaling has proven to be successful in mouse polymicrobial sepsis. To confirm that such therapy might be translated to septic patients, we analyzed metabolic perturbations in the liver of a porcine fecal peritonitis model. Resuscitation with fluids, vasopressor, antimicrobial therapy and abdominal lavage were applied to the pigs in order to mimic human clinical care. By using RNA-seq, we detected downregulated PPARɑ signaling in the livers of septic pigs and that reduced PPARɑ levels correlated well with disease severity. As PPARɑ regulates the expression of many genes involved in fatty acid oxidation, the reduced expression of these target genes, concomitant with increased free fatty acids in plasma and ectopic lipid deposition in the liver, was observed. The results obtained with pigs are in agreement with earlier observations seen in mice and support the potential of targeting defective PPARɑ signaling in clinical research.https://www.mdpi.com/2073-4409/11/24/4080sepsisswinemetabolismPPARɑfree fatty acids |
| spellingShingle | Jolien Vandewalle Bruno Garcia Steven Timmermans Tineke Vanderhaeghen Lise Van Wyngene Melanie Eggermont Hester Dufoor Céline Van Dender Fëllanza Halimi Siska Croubels Antoine Herpain Claude Libert Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic Shock Cells sepsis swine metabolism PPARɑ free fatty acids |
| title | Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic Shock |
| title_full | Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic Shock |
| title_fullStr | Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic Shock |
| title_full_unstemmed | Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic Shock |
| title_short | Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic Shock |
| title_sort | hepatic peroxisome proliferator activated receptor alpha dysfunction in porcine septic shock |
| topic | sepsis swine metabolism PPARɑ free fatty acids |
| url | https://www.mdpi.com/2073-4409/11/24/4080 |
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