Peroxisome Proliferator-activated Receptor-γ Coactivator 1-α (PGC1α) Protects against Experimental Murine Colitis

Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PG CM) is the primary regulator of mitochondrial biogenesis and was recently found to be highly expressed within the intestinal epithelium. PGC1 alpha is decreased in the intestinal epithelium of patients with inflammatory bowel disease, but its role in pathogenesis is uncertain. We now hypothesize that PGC1 alpha protects against the development of colitis and helps to maintain the integrity of the intestinal barrier. We selectively deleted PGC1 alpha from the intestinal epithelium of mice by breeding a PGC1 alpha(loxP/loxP) mouse with a villin-cre mouse. Their progeny (pGC1 alpha(Delta IEC) mice) were subjected to 2% dextran sodium sulfate (DSS) colitis for 7 days. The SIRT1 agonist SRT1720 was used to enhance PGC1 alpha activation in wild-type mice during DSS exposure. Mice lacking PGC1 alpha within the intestinal epithelium were more susceptible to DSS colitis than their wild-type littermates. Pharmacologic activation of PGC1 alpha successfully ameliorated disease and restored mitochondrial integrity. These findings suggest that a depletion of PGC1 alpha in the intestinal epithelium contributes to inflammatory changes through a failure of mitochondrial structure and function as well as a breakdown of the intestinal barrier, which leads to increased bacterial translocation. PGC1 alpha induction helps to maintain mitochondrial integrity, enhance intestinal barrier function, and decrease inflammation.