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

Kellie E. Cunningham, Garret Vincent, Chhinder P. Sodhi, Elizabeth A. Novak, Sarangarajan Ranganathan, Charlotte E. Egan, Donna Beer Stolz, Matthew B. Rogers, Brian Firek, Michael J. Morowitz, George K. Gittes, Brian S. Zuckerbraun, David J. Hackam, Kevin P. Mollen

Research output: Contribution to journalArticlepeer-review

Abstract

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is the primary regulator of mitochondrial biogenesis and was recently found to be highly expressed within the intestinal epithelium. PGC1α is decreased in the intestinal epithelium of patients with inflammatory bowel disease, but its role in pathogenesis is uncertain. We now hypothesize that PGC1α protects against the development of colitis and helps to maintain the integrity of the intestinal barrier.Weselectively deleted PGC1α from the intestinal epithelium of mice by breeding a PGC1αloxP/loxP mouse with a villin-cre mouse. Their progeny (PGC1αIEC mice) were subjected to 2% dextran sodium sulfate (DSS) colitis for 7 days. The SIRT1 agonist SRT1720 was used to enhance PGC1α activation in wild-type mice during DSS exposure. Mice lacking PGC1α within the intestinal epithelium were more susceptible to DSS colitis than their wild-type littermates. Pharmacologic activation of PGC1α successfully ameliorated disease and restored mitochondrial integrity. These findings suggest that a depletion of PGC1α 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. PGC1α induction helps to maintain mitochondrial integrity, enhance intestinal barrier function, and decrease inflammation.

Original languageEnglish (US)
Pages (from-to)10184-10200
Number of pages17
JournalJournal of Biological Chemistry
Volume291
Issue number19
DOIs
StatePublished - May 6 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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