A medium-chain fatty acid analogue prevents endotoxin liver injury in a murine model
Abstract Parenteral nutrition (PN) is lifesaving for patients with short bowel syndrome and other gastrointestinal disorders, however long-term use may lead to complications including hepatosteatosis and sepsis. We have previously demonstrated the anti-steatotic, -fibrotic, and -inflammatory propert...
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Nature Portfolio
2025-04-01
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| Online Access: | https://doi.org/10.1038/s41598-025-98200-y |
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| author | Sarah Z. Wang Thomas I. Hirsch Scott C. Fligor Savas T. Tsikis Amy Pan Mikayla Quigley Paul D. Mitchell Kathleen M. Gura David A. Fraser Mark Puder |
| author_facet | Sarah Z. Wang Thomas I. Hirsch Scott C. Fligor Savas T. Tsikis Amy Pan Mikayla Quigley Paul D. Mitchell Kathleen M. Gura David A. Fraser Mark Puder |
| author_sort | Sarah Z. Wang |
| collection | DOAJ |
| description | Abstract Parenteral nutrition (PN) is lifesaving for patients with short bowel syndrome and other gastrointestinal disorders, however long-term use may lead to complications including hepatosteatosis and sepsis. We have previously demonstrated the anti-steatotic, -fibrotic, and -inflammatory properties of SEFA-6179, an engineered medium-chain fatty acid analogue. We hypothesized that SEFA-6179 treatment would protect against endotoxin-induced liver injury in a murine model of PN-induced hepatosteatosis. C57Bl/6J mice were administered a high-carbohydrate liquid diet plus intravenous lipid emulsion (Intralipid, 4 g fat/kg/d) or intravenous saline for 19 days to induce hepatosteatosis. SEFA-6179 (100 mg/kg) or vehicle (MCT/medium-chain triglyceride) was administered via oral gavage for four days leading up to intraperitoneal challenge with lipopolysaccharide (15 mg/kg) or saline on day 19. Age-matched, chow-fed controls received the same treatments. The primary outcome was liver biomarkers: alanine aminotransferase and aspartate aminotransferase. Pro-inflammatory cytokines, IL-6, TNF-alpha, and monocyte chemoattractant protein (MCP1), were analyzed. Liver immunofluorescence staining was performed to evaluate macrophage phenotypes. In endotoxin-challenged mice, pre-treatment with SEFA-6179 lowered liver enzymes and pro-inflammatory cytokine levels compared to vehicle. On liver histology, SEFA-6179 pre-treatment led to greater polarization of M1/pro-inflammatory macrophages to an M2/anti-inflammatory phenotype compared to vehicle. SEFA-6179 is currently in Phase II clinical trials. These findings support the potential application of SEFA-6179 in high-risk, PN-dependent patients. |
| format | Article |
| id | doaj-art-9caec539ba4847f6b1b666fa122d6ee7 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-9caec539ba4847f6b1b666fa122d6ee72025-08-20T03:13:57ZengNature PortfolioScientific Reports2045-23222025-04-0115111210.1038/s41598-025-98200-yA medium-chain fatty acid analogue prevents endotoxin liver injury in a murine modelSarah Z. Wang0Thomas I. Hirsch1Scott C. Fligor2Savas T. Tsikis3Amy Pan4Mikayla Quigley5Paul D. Mitchell6Kathleen M. Gura7David A. Fraser8Mark Puder9Boston Children’s HospitalBoston Children’s HospitalBoston Children’s HospitalBoston Children’s HospitalBoston Children’s HospitalBoston Children’s HospitalBoston Children’s HospitalBoston Children’s HospitalNorthSea TherapeuticsBoston Children’s HospitalAbstract Parenteral nutrition (PN) is lifesaving for patients with short bowel syndrome and other gastrointestinal disorders, however long-term use may lead to complications including hepatosteatosis and sepsis. We have previously demonstrated the anti-steatotic, -fibrotic, and -inflammatory properties of SEFA-6179, an engineered medium-chain fatty acid analogue. We hypothesized that SEFA-6179 treatment would protect against endotoxin-induced liver injury in a murine model of PN-induced hepatosteatosis. C57Bl/6J mice were administered a high-carbohydrate liquid diet plus intravenous lipid emulsion (Intralipid, 4 g fat/kg/d) or intravenous saline for 19 days to induce hepatosteatosis. SEFA-6179 (100 mg/kg) or vehicle (MCT/medium-chain triglyceride) was administered via oral gavage for four days leading up to intraperitoneal challenge with lipopolysaccharide (15 mg/kg) or saline on day 19. Age-matched, chow-fed controls received the same treatments. The primary outcome was liver biomarkers: alanine aminotransferase and aspartate aminotransferase. Pro-inflammatory cytokines, IL-6, TNF-alpha, and monocyte chemoattractant protein (MCP1), were analyzed. Liver immunofluorescence staining was performed to evaluate macrophage phenotypes. In endotoxin-challenged mice, pre-treatment with SEFA-6179 lowered liver enzymes and pro-inflammatory cytokine levels compared to vehicle. On liver histology, SEFA-6179 pre-treatment led to greater polarization of M1/pro-inflammatory macrophages to an M2/anti-inflammatory phenotype compared to vehicle. SEFA-6179 is currently in Phase II clinical trials. These findings support the potential application of SEFA-6179 in high-risk, PN-dependent patients.https://doi.org/10.1038/s41598-025-98200-yParenteral nutritionLiver steatosisInflammationFatty acid |
| spellingShingle | Sarah Z. Wang Thomas I. Hirsch Scott C. Fligor Savas T. Tsikis Amy Pan Mikayla Quigley Paul D. Mitchell Kathleen M. Gura David A. Fraser Mark Puder A medium-chain fatty acid analogue prevents endotoxin liver injury in a murine model Scientific Reports Parenteral nutrition Liver steatosis Inflammation Fatty acid |
| title | A medium-chain fatty acid analogue prevents endotoxin liver injury in a murine model |
| title_full | A medium-chain fatty acid analogue prevents endotoxin liver injury in a murine model |
| title_fullStr | A medium-chain fatty acid analogue prevents endotoxin liver injury in a murine model |
| title_full_unstemmed | A medium-chain fatty acid analogue prevents endotoxin liver injury in a murine model |
| title_short | A medium-chain fatty acid analogue prevents endotoxin liver injury in a murine model |
| title_sort | medium chain fatty acid analogue prevents endotoxin liver injury in a murine model |
| topic | Parenteral nutrition Liver steatosis Inflammation Fatty acid |
| url | https://doi.org/10.1038/s41598-025-98200-y |
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