title: Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice.
abstract: OBJECTIVE
  A high serum level of saturated free fatty acids (FFAs) is associated with the development of nonalcoholic fatty liver disease (NAFLD). X-box binding protein-1 (XBP-1) is activated by FFA treatment upon splicing. XBP-1 is a transcription factor induced by the endoplasmic reticulum (ER) stress sensor endoribonuclease inositol-requiring enzyme 1 alpha (IRE1α). However, the role of XBP-1 in NAFLD remains relatively unexplored. Toyocamycin was recently reported to attenuate the activation of XBP-1, possibly by inducing a conformational change in IRE1α. In this study, we examined the effect of toyocamycin on hepatocyte lipoapoptosis and steatosis. We also explored the effects of toyocamycin in a mouse model of NAFLD.
  
  
  METHODS
  Huh-7 cells and isolated rat primary hepatocytes were treated with palmitic acid (PA), which is a saturated FFA, in the presence or absence of toyocamycin. In addition, male C57BL/6J mice were fed a diet rich in saturated fat, fructose, and cholesterol (FFC) for 4 months, after which the effect of toyocamycin was assessed.
  
  
  RESULTS
  Toyocamycin attenuated FFA-induced steatosis. It also significantly reduced PA-induced hepatocyte lipoapoptosis. In addition, toyocamycin reduced the expression of cytosine-cytosine-adenosine-adenosine-thymidine enhancer-binding protein homologous protein (CHOP), which is a key player in ER stress-mediated apoptosis, as well as its downstream cell death modulator, death receptor 5. In the in vivo study, toyocamycin ameliorated the liver injury caused by FFC-induced NAFLD. It also reduced hepatic steatosis and the expression of lipogenic genes.
  
  
  CONCLUSIONS
  The data we obtained suggest that toyocamycin attenuates hepatocyte lipogenesis and ameliorates NAFLD in vivo and may therefore be beneficial in the treatment of NAFLD in humans.
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takahara
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Akazawa
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Tabuchi
authors.affiliation: Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Miyaaki
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Youko
authors.initials: Y
authors.lastname: Kido
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kanda
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Naota
authors.initials: N
authors.lastname: Taura
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ohnita
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Fuminao
authors.initials: F
authors.lastname: Takeshima
authors.affiliation: Department of Surgery, Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Surgery, Nagasaki University, Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Eguchi
authors.affiliation: Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Division of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D019308:Palmitic Acid / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014127:Toyocamycin / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D019308:Palmitic Acid; D014127:Toyocamycin