A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure–Associated Liver Disease in Preterm Yorkshire Piglets

Abstract

At least 20 to 30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD. Preterm Yorkshire piglets were delivered by caesarean section and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium chain triglycerides (MCT) vehicle control or SEFA-6179. Compared to MCT vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs. <0.2 mg/dL, P=0.01; total bilirubin: 2.7 vs. 0.4 mg/dL, P=0.02; gamma glutamyl transferase 172 vs. 30 U/L, P=0.01). SEFA-6179 also prevented steatosis (45.6 vs. 13.9 mg triglycerides/g liver tissue, P=0.009), reduced bile duct proliferation (1.6 vs. 0.5% area cytokeratin 7 positive, P=0.009), and reduced fibrosis assessed by a masked pathologist (median Ishak score 3 vs. 1, P=0.007). RNA-Seq of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist). In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis, and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.