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J Biol Chem. 2016 May 6;291(19):10184-200. doi: 10.1074/jbc.M115.688812. Epub 2016 Mar 11.

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

Author information

1
the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
2
the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, From the Division of Pediatric Surgery, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
3
the Department of Surgery, The Johns Hopkins University, Baltimore, Maryland 21218.
4
the Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, and.
5
the Center for Biologic Imaging, University or Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
6
the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, From the Division of Pediatric Surgery, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, kevin.mollen@chp.edu.

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. We selectively deleted PGC1α from the intestinal epithelium of mice by breeding a PGC1α(loxP/loxP) mouse with a villin-cre mouse. Their progeny (PGC1α(ΔIEC) 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.

KEYWORDS:

bacterial pathogenesis; inflammatory bowel disease (IBD); intestinal epithelium; mitochondria; oxidative stress

PMID:
26969166
PMCID:
PMC4858969
DOI:
10.1074/jbc.M115.688812
[Indexed for MEDLINE]
Free PMC Article

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