O1094: Intestine-specific Peroxisome Proliferator-activated Receptor-alpha Deletion Modifies Structural Adaptation but Not Liver Injury Following Massive Enterectomy

Background: Resection-associated liver steatosis, injury, and fibrosis is a devastating complication associated with massive small bowel resection (SBR). Peroxisome proliferator-activated receptor-alpha (PPARα) is a key regulator of lipid transport and metabolism whose expression is selectively increased in the intestine after SBR. Here we asked if attenuating intestinal PPARα signaling would modify liver injury after SBR.

Methods: Pparα was deleted selectively in adult intestine using tamoxifen-inducible ER-Vil-Cre. Pparα intestinal knockout (iKO; n=15; 8 female, 7 male) and littermate control (Pparα fl/fl; n=9; 6 female, 3 male) mice underwent 50% SBR at 8 weeks. Tamoxifen was administered to both groups one week prior to operation. Body composition was determined by magnetic resonance imaging and tissues were harvested at 10 weeks after SBR. Intestinal PPARα deletion was confirmed by Western blot. Crypts and villi were measured on histological sections to assess intestinal adaptation. Liver injury was assessed by Sirius Red staining of liver, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and qPCR expression of fibrosis-associated genes, Col1a1 and Acta2. Paired and unpaired t-tests were used for statistical analyses. Studies were approved by the institution’s Animal Studies Committee (Protocol #20-0197).

Results: Pparα iKO and control mice exhibited similar weight trends after SBR (Figure 1A). After 10 weeks, Pparα iKO mice exhibited greater lean mass compared to controls, potentially due to impaired fat absorption (p=0.03, Figure 1B). All mice demonstrated intestinal adaptation with increased villus height and crypt depth; however, Pparα iKO mice exhibited decreased villus growth at 10 weeks compared to littermate controls (p=0.0014, Figure 1C). Liver fibrosis was similar between groups as assessed by Sirius Red staining (Figure 2A) and expression of Col1a1 and Acta2 (Figure 2B). Serum ALT levels were similar by genotype, and AST levels were higher in Pparα iKO mice compared to littermate controls (Figure 2C). Subgroup analyses by gender confirmed similar trends.

Conclusion: Inducible intestinal deletion of PPARα, a major regulator of intestinal lipid metabolism, influences structural adaptation but does not mitigate liver injury after SBR. These findings suggest that enterocyte PPARα signaling in adult mice is dispensable for liver injury following SBR. Our findings are critical for understanding the contribution of intestinal lipid metabolic signaling pathways to the pathogenesis of hepatic injury associated with short gut syndrome.