title: Peroxisome Proliferator-activated Receptor-γ Coactivator 1-α (PGC1α) Protects against Experimental Murine Colitis.
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.
authors.affiliation: the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors.forename: Kellie E
authors.initials: KE
authors.lastname: Cunningham
authors.affiliation: 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.
authors.forename: Garret
authors.initials: G
authors.lastname: Vincent
authors.affiliation: the Department of Surgery, The Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: Chhinder P
authors.initials: CP
authors.lastname: Sodhi
authors.affiliation: 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.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Novak
authors.affiliation: the Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, and.
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: 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.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Egan
authors.affiliation: the Center for Biologic Imaging, University or Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors.forename: Donna Beer
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: 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.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Rogers
authors.affiliation: 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.
authors.forename: Brian
authors.initials: B
authors.lastname: Firek
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morowitz
authors.affiliation: 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.
authors.forename: George K
authors.initials: GK
authors.lastname: Gittes
authors.affiliation: the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
authors.affiliation: the Department of Surgery, The Johns Hopkins University, Baltimore, Maryland 21218.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.affiliation: 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.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Mollen
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D016264:Dextran Sulfate
keywords: bacterial pathogenesis; inflammatory bowel disease (IBD); intestinal epithelium; mitochondria; oxidative stress