Indomethacin suppresses LAMP-2 expression and induces lipophagy and lipoapoptosis in rat enterocytes via the ER stress pathway

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• 作者：Ken Narabayashi ; Yuko Ito ; Nabil Eid ; Kentaro Maemura…
• 关键词：Enterocytes ; Indomethacin ; LAMP ; 2 ; Lipid droplet ; Lipophagy ; Lipoapoptosis ; Endoplasmic reticulum stress ; 4 ; Phenylbutyrate ; LC3 puncta
• 刊名：Journal of Gastroenterology
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：50
• 期：5
• 页码：541-554
• 全文大小：7,690 KB
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• 作者单位：Ken Narabayashi (1)
  Yuko Ito (2)
  Nabil Eid (2)
  Kentaro Maemura (2)
  Takuya Inoue (1)
  Toshihisa Takeuchi (1)
  Yoshinori Otsuki (2)
  Kazuhide Higuchi (1)
  
  1. Second Department of Internal Medicine, Osaka Medical College, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
  2. Division of Life Sciences, Department of Anatomy and Cell Biology, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Gastroenterology
  Oncology
  Surgical Oncology
  Hepatology
  Internal Medicine
  Colorectal Surgery
  
• 出版者：Springer Japan
• ISSN：1435-5922

文摘

Background Indomethacin enhances small intestinal epithelial cell apoptosis, which may account for mucosal ulceration. However, the involvement of autophagy in indomethacin-induced enterocyte damage is unreported. Methods Using light microscopy and electron microscopy techniques, Western blot analysis, and pharmacological inhibition of autophagy, we investigated the autophagic response of cultured rat enterocytes to indomethacin treatment (200?μM) at various time points. Furthermore, autophagy was examined in enterocytes of rats given indomethacin by gavage (10?mg/kg). Results Our data indicate that indomethacin induced accumulation of cytoplasmic lipid droplets (LDs) in cultured enterocytes, which was associated with time-dependent autophagic responses. Initially (0-?h), mediated by endoplasmic reticulum stress and suppression of mammalian target of rapamycin, a predominant cytoprotective lipophagy was activated in indomethacin-treated enterocytes, as evidenced by induction and colocalization of LC3-II with LDs, excessive formation of autophagosomes sequestering LDs (autolipophagosomes; ALPs), and decreased viability of enterocytes on blocking autophagy with 3-methyladenine. On prolonged exposure to indomethacin (6-4?h), there was a decrease of LAMP-2 expression in enterocytes coupled with accumulation of ALPs and LDs with fewer autolysosomes in addition to an elevation of lipoapoptosis. These time-dependent autophagic and apoptotic responses to indomethacin treatment were detected in enterocytes of indomethacin-treated rats, confirming in vitro results. Conclusions The findings of this study describe a novel mechanism of enterocyte damage by indomethacin mediated by endoplasmic reticulum stress, accumulation of LDs, and subsequent activation of the early phase of cytoprotective lipophagy. This is followed by a late phase characterized by reduced expression of lysosomal autophagic proteins, accumulation of ALPs, and enhanced lipoapoptosis.