Prohibitin Is a Novel Regulator of Antioxidant Response That Attenuates Colonic Inflammation in Mice

Arianne L. Theiss, Matam Vijay Kumar, Tracy S. Obertone, Dean P. Jones, Jason M. Hansen, Andrew T. Gewirtz, Didier Merlin, Shanthi V. Sitaraman

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Background & Aims: Increased free radicals and/or impaired antioxidant defenses have been shown to play a pathogenetic role in human and animal models of inflammatory bowel disease. Our previous studies showed that prohibitin (PHB) levels are decreased during colitis and that cultured intestinal epithelial cells overexpressing PHB are protected from oxidative stress. This study investigated the effect of intestinal epithelial cell-specific PHB overexpression on oxidative stress associated with experimental colitis and the potential mechanism by which PHB functions as an antioxidant using PHB transgenic mice. Methods: Colitis was induced using 2 established mouse models (Salmonella typhimurium and dextran sodium sulfate) in PHB transgenic mice and wild-type littermates. Oxidative stress was determined by measuring glutathione and protein carbonyl levels in the cecum or colon. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional regulator of oxidant responses, expression, and activation, was assessed in colon mucosa and cultured intestinal epithelial cells overexpressing PHB. Results: Cells overexpressing PHB showed sustained Nrf2 nuclear accumulation and DNA binding during oxidant stress. PHB transgenic mice exhibited decreased oxidative stress and colitis and increased Nrf2 messenger RNA expression, nuclear protein translocation, and DNA binding compared with wild-type littermates during colitis. Conclusions: These results show that PHB is a regulator of Nrf2 expression in intestinal epithelial cells during oxidative conditions and prevents inflammation-associated oxidative stress and injury through sustained activation of Nrf2. Our data show that PHB is a novel regulator of antioxidants and suggest that restoration of PHB levels represents a potential therapeutic approach in inflammatory bowel disease.

Original languageEnglish (US)
JournalGastroenterology
Volume137
Issue number1
DOIs
StatePublished - Jan 1 2009

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Antioxidants
Inflammation
Colitis
Oxidative Stress
Epithelial Cells
Transgenic Mice
Inflammatory Bowel Diseases
Oxidants
prohibitin
Colon
Dextran Sulfate
Cecum
DNA
Protein Transport
Salmonella typhimurium
Intestinal Mucosa
Nuclear Proteins
Free Radicals
Glutathione
Animal Models

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Theiss, A. L., Kumar, M. V., Obertone, T. S., Jones, D. P., Hansen, J. M., Gewirtz, A. T., ... Sitaraman, S. V. (2009). Prohibitin Is a Novel Regulator of Antioxidant Response That Attenuates Colonic Inflammation in Mice. Gastroenterology, 137(1). https://doi.org/10.1053/j.gastro.2009.03.033
Theiss, Arianne L. ; Kumar, Matam Vijay ; Obertone, Tracy S. ; Jones, Dean P. ; Hansen, Jason M. ; Gewirtz, Andrew T. ; Merlin, Didier ; Sitaraman, Shanthi V. / Prohibitin Is a Novel Regulator of Antioxidant Response That Attenuates Colonic Inflammation in Mice. In: Gastroenterology. 2009 ; Vol. 137, No. 1.
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abstract = "Background & Aims: Increased free radicals and/or impaired antioxidant defenses have been shown to play a pathogenetic role in human and animal models of inflammatory bowel disease. Our previous studies showed that prohibitin (PHB) levels are decreased during colitis and that cultured intestinal epithelial cells overexpressing PHB are protected from oxidative stress. This study investigated the effect of intestinal epithelial cell-specific PHB overexpression on oxidative stress associated with experimental colitis and the potential mechanism by which PHB functions as an antioxidant using PHB transgenic mice. Methods: Colitis was induced using 2 established mouse models (Salmonella typhimurium and dextran sodium sulfate) in PHB transgenic mice and wild-type littermates. Oxidative stress was determined by measuring glutathione and protein carbonyl levels in the cecum or colon. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional regulator of oxidant responses, expression, and activation, was assessed in colon mucosa and cultured intestinal epithelial cells overexpressing PHB. Results: Cells overexpressing PHB showed sustained Nrf2 nuclear accumulation and DNA binding during oxidant stress. PHB transgenic mice exhibited decreased oxidative stress and colitis and increased Nrf2 messenger RNA expression, nuclear protein translocation, and DNA binding compared with wild-type littermates during colitis. Conclusions: These results show that PHB is a regulator of Nrf2 expression in intestinal epithelial cells during oxidative conditions and prevents inflammation-associated oxidative stress and injury through sustained activation of Nrf2. Our data show that PHB is a novel regulator of antioxidants and suggest that restoration of PHB levels represents a potential therapeutic approach in inflammatory bowel disease.",
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Theiss, AL, Kumar, MV, Obertone, TS, Jones, DP, Hansen, JM, Gewirtz, AT, Merlin, D & Sitaraman, SV 2009, 'Prohibitin Is a Novel Regulator of Antioxidant Response That Attenuates Colonic Inflammation in Mice', Gastroenterology, vol. 137, no. 1. https://doi.org/10.1053/j.gastro.2009.03.033

Prohibitin Is a Novel Regulator of Antioxidant Response That Attenuates Colonic Inflammation in Mice. / Theiss, Arianne L.; Kumar, Matam Vijay; Obertone, Tracy S.; Jones, Dean P.; Hansen, Jason M.; Gewirtz, Andrew T.; Merlin, Didier; Sitaraman, Shanthi V.

In: Gastroenterology, Vol. 137, No. 1, 01.01.2009.

Research output: Contribution to journalArticle

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AU - Theiss, Arianne L.

AU - Kumar, Matam Vijay

AU - Obertone, Tracy S.

AU - Jones, Dean P.

AU - Hansen, Jason M.

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AU - Merlin, Didier

AU - Sitaraman, Shanthi V.

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N2 - Background & Aims: Increased free radicals and/or impaired antioxidant defenses have been shown to play a pathogenetic role in human and animal models of inflammatory bowel disease. Our previous studies showed that prohibitin (PHB) levels are decreased during colitis and that cultured intestinal epithelial cells overexpressing PHB are protected from oxidative stress. This study investigated the effect of intestinal epithelial cell-specific PHB overexpression on oxidative stress associated with experimental colitis and the potential mechanism by which PHB functions as an antioxidant using PHB transgenic mice. Methods: Colitis was induced using 2 established mouse models (Salmonella typhimurium and dextran sodium sulfate) in PHB transgenic mice and wild-type littermates. Oxidative stress was determined by measuring glutathione and protein carbonyl levels in the cecum or colon. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional regulator of oxidant responses, expression, and activation, was assessed in colon mucosa and cultured intestinal epithelial cells overexpressing PHB. Results: Cells overexpressing PHB showed sustained Nrf2 nuclear accumulation and DNA binding during oxidant stress. PHB transgenic mice exhibited decreased oxidative stress and colitis and increased Nrf2 messenger RNA expression, nuclear protein translocation, and DNA binding compared with wild-type littermates during colitis. Conclusions: These results show that PHB is a regulator of Nrf2 expression in intestinal epithelial cells during oxidative conditions and prevents inflammation-associated oxidative stress and injury through sustained activation of Nrf2. Our data show that PHB is a novel regulator of antioxidants and suggest that restoration of PHB levels represents a potential therapeutic approach in inflammatory bowel disease.

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