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An engineered medium-chain fatty acid analogue protects against lipopolysaccharide-induced liver injury in a murine model of intestinal failure-associated liver disease
Sarah Z Wang
1,
2, Thomas I Hirsch
1,
2, Amy Pan
1,
2, Mikayla Quigley
1,
2, Hiroko Kishikawa
1,
2, Savas T Tsikis
1,
2, Scott C Fligor
1,
2, Paul D Mitchell
2,
3, Kathleen M Gura
2,
4, Mark Puder
1,
2
1Vascular Biology Program & Department of Surgery, Boston Children’s Hospital, Boston, MA, 2Harvard Medical School, Boston, MA, 3Biostatistics and Research Design Center, Boston Children’s Hospital, Boston, MA, 4Department of Pharmacy, Division of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, MA
Background: Parenteral nutrition (PN)-dependent patients with short bowel syndrome may develop life-threatening complications, including intestinal failure-associated liver disease (IFALD) and central line-associated bloodstream infections (CLABSIs). IFALD pathophysiology involves hepatosteatosis and endotoxin-driven inflammation. Animal models have demonstrated the anti-inflammatory properties of SEFA-6179, an engineered medium-chain fatty acid analogue. We hypothesized that SEFA-6179 protects against lipopolysaccharide (LPS)-induced liver injury in a murine model of PN-induced hepatosteatosis.
Methods: Eight-week-old C57BL/6J mice received oral fat-free PN and intravenous lipid emulsion (Intralipid, 4g fat/kg/d) or saline for 19 days. Mice received oral SEFA-6179 (100mg/kg) or vehicle (MCT/medium-chain triglyceride) daily on D15-18. Mice received intraperitoneal LPS (15mg/kg) or saline 6 hours before sacrifice on D19. Chow-fed groups were treated in parallel. The primary outcome was assessment of liver injury via aminotransferase (ALT) and aspartate aminotransferase (AST). IL-6 and TNF-alpha levels were assayed.
Results: In LPS-challenged mice, SEFA-6179 pre-treatment normalized liver enzymes compared to vehicle (Figure 1). SEFA-6179 pre-treatment reduced levels of pro-inflammatory cytokines, IL-6 and TNF-alpha (Figure 2).
Conclusions: Pre-treatment with SEFA-6179 normalized liver enzymes and pro-inflammatory cytokines, IL-6 and TNF-alpha, compared to vehicle in a murine model of PN-associated hepatosteatosis and LPS-induced inflammation. SEFA-6179 is in a Phase II clinical trial in patients with IFALD.
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