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FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis

Nonalcoholic steatohepatitis (NASH) patients have elevated plasma saturated free fatty acid levels. These toxic fatty acids can induce liver cell death and our recent results demonstrated that the biliary epithelium may be susceptible to lipotoxicity. Here, we explored the molecular mechanisms of ch...

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Autores principales: Natarajan, Sathish Kumar, Stringham, Bailey A., Mohr, Ashley M., Wehrkamp, Cody J., Lu, Sizhao, Phillippi, Mary Anne, Harrison-Findik, Dee, Mott, Justin L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Biochemistry and Molecular Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408604/
https://www.ncbi.nlm.nih.gov/pubmed/28250026
http://dx.doi.org/10.1194/jlr.M071357
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author Natarajan, Sathish Kumar
Stringham, Bailey A.
Mohr, Ashley M.
Wehrkamp, Cody J.
Lu, Sizhao
Phillippi, Mary Anne
Harrison-Findik, Dee
Mott, Justin L.
author_facet Natarajan, Sathish Kumar
Stringham, Bailey A.
Mohr, Ashley M.
Wehrkamp, Cody J.
Lu, Sizhao
Phillippi, Mary Anne
Harrison-Findik, Dee
Mott, Justin L.
author_sort Natarajan, Sathish Kumar
collection PubMed
description Nonalcoholic steatohepatitis (NASH) patients have elevated plasma saturated free fatty acid levels. These toxic fatty acids can induce liver cell death and our recent results demonstrated that the biliary epithelium may be susceptible to lipotoxicity. Here, we explored the molecular mechanisms of cholangiocyte lipoapoptosis in cell culture and in an animal model of NASH. Treatment of cholangiocytes with palmitate (PA) showed increased caspase 3/7 activity and increased levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3, demonstrating cholangiocyte lipoapoptosis. Interestingly, treatment with PA significantly increased the levels of microRNA miR-34a, a pro-apoptotic microRNA known to be elevated in NASH. PA induction of miR-34a was abolished in cholangiocytes transduced with forkhead family of transcription factor class O (FoxO)3 shRNA, demonstrating that FoxO3 activation is upstream of miR-34a and suggesting that FoxO3 is a novel transcriptional regulator of miR-34a. Further, anti-miR-34a protected cholangiocytes from PA-induced lipoapoptosis. Direct and indirect targets of miR-34a, such as SIRT1, receptor tyrosine kinase (MET), Kruppel-like factor 4, fibroblast growth factor receptor (FGFR)1, and FGFR4, were all decreased in PA-treated cholangiocytes. SIRT1 and MET were partially rescued by a miR-34a antagonist. Cholangiocyte apoptosis and miR-34a were dramatically increased in the liver of mice with early histologic features of NASH. Our study provides evidence for the pro-apoptotic role of miR-34a in PA-induced cholangiocyte lipoapoptosis in culture and in the liver.
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spelling pubmed-54086042017-05-04 FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis Natarajan, Sathish Kumar Stringham, Bailey A. Mohr, Ashley M. Wehrkamp, Cody J. Lu, Sizhao Phillippi, Mary Anne Harrison-Findik, Dee Mott, Justin L. J Lipid Res Research Articles Nonalcoholic steatohepatitis (NASH) patients have elevated plasma saturated free fatty acid levels. These toxic fatty acids can induce liver cell death and our recent results demonstrated that the biliary epithelium may be susceptible to lipotoxicity. Here, we explored the molecular mechanisms of cholangiocyte lipoapoptosis in cell culture and in an animal model of NASH. Treatment of cholangiocytes with palmitate (PA) showed increased caspase 3/7 activity and increased levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3, demonstrating cholangiocyte lipoapoptosis. Interestingly, treatment with PA significantly increased the levels of microRNA miR-34a, a pro-apoptotic microRNA known to be elevated in NASH. PA induction of miR-34a was abolished in cholangiocytes transduced with forkhead family of transcription factor class O (FoxO)3 shRNA, demonstrating that FoxO3 activation is upstream of miR-34a and suggesting that FoxO3 is a novel transcriptional regulator of miR-34a. Further, anti-miR-34a protected cholangiocytes from PA-induced lipoapoptosis. Direct and indirect targets of miR-34a, such as SIRT1, receptor tyrosine kinase (MET), Kruppel-like factor 4, fibroblast growth factor receptor (FGFR)1, and FGFR4, were all decreased in PA-treated cholangiocytes. SIRT1 and MET were partially rescued by a miR-34a antagonist. Cholangiocyte apoptosis and miR-34a were dramatically increased in the liver of mice with early histologic features of NASH. Our study provides evidence for the pro-apoptotic role of miR-34a in PA-induced cholangiocyte lipoapoptosis in culture and in the liver. The American Society for Biochemistry and Molecular Biology 2017-05 2017-04-28 /pmc/articles/PMC5408604/ /pubmed/28250026 http://dx.doi.org/10.1194/jlr.M071357 Text en Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc. http://creativecommons.org/licenses/by/4.0/ Author’s Choice—Final version free via Creative Commons CC-BY license.
spellingShingle Research Articles
Natarajan, Sathish Kumar
Stringham, Bailey A.
Mohr, Ashley M.
Wehrkamp, Cody J.
Lu, Sizhao
Phillippi, Mary Anne
Harrison-Findik, Dee
Mott, Justin L.
FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis
title FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis
title_full FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis
title_fullStr FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis
title_full_unstemmed FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis
title_short FoxO3 increases miR-34a to cause palmitate-induced cholangiocyte lipoapoptosis
title_sort foxo3 increases mir-34a to cause palmitate-induced cholangiocyte lipoapoptosis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408604/
https://www.ncbi.nlm.nih.gov/pubmed/28250026
http://dx.doi.org/10.1194/jlr.M071357
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