title: PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine.
abstract: The mucosa of the small intestine is renewed completely every 3-5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain. ROS homeostasis is maintained to control cell death and is finely tuned by an inducible antioxidant program. Here we show that peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β) is highly expressed in the intestinal epithelium and possesses dual activity, stimulating mitochondrial biogenesis and oxygen consumption while inducing antioxidant enzymes. To study the role of PGC-1β gain and loss of function in the gut, we generated both intestinal-specific PGC-1β transgenic and PGC-1β knockout mice. Mice overexpressing PGC-1β present a peculiar intestinal morphology with very long villi resulting from increased enterocyte lifespan and also demonstrate greater tumor susceptibility, with increased tumor number and size when exposed to carcinogens. PGC-1β knockout mice are protected from carcinogenesis. We show that PGC-1β triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1β in the gut acts as an adaptive self-point regulator, capable of providing a balance between enhanced mitochondrial activity and protection from increased ROS production.
authors.affiliation: Fondazione Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Bellafante
authors.affiliation: Fondazione Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy;
authors.forename: Annalisa
authors.initials: A
authors.lastname: Morgano
authors.affiliation: Fondazione Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy;
authors.forename: Lorena
authors.initials: L
authors.lastname: Salvatore
authors.affiliation: Fondazione Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Murzilli
authors.affiliation: Fondazione Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Tullio
authors.affiliation: Fondazione Mario Negri Sud, 66030 Santa Maria Imbaro (Chieti), Italy;
authors.forename: Andria
authors.initials: A
authors.lastname: D'Orazio
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, and.
authors.forename: Dominga
authors.initials: D
authors.lastname: Latorre
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, and gaetano.villani@uniba.it antonio.moschetta@uniba.it.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Villani
authors.affiliation: Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70121 Bari, Italy; and National Cancer Research Center, Istituto Oncologico "Giovanni Paolo II," 70124 Bari, Italy gaetano.villani@uniba.it antonio.moschetta@uniba.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D063646:Carcinogenesis; D003110:Colonic Neoplasms / Q000473:pathology*; D004579:Electron Transport; D020895:Enterocytes / Q000166:cytology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006706:Homeostasis; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology*; D007421:Intestine, Small / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D010100:Oxygen
keywords: colon cancer; gene expression; molecular pathology; nuclear receptors