Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice

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...

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Published in:PloS one 2017-03, Vol.12 (3), p.e0170591-e0170591
Main Authors: Takahara, Ikuko, Akazawa, Yuko, Tabuchi, Maiko, Matsuda, Katsuya, Miyaaki, Hisamitsu, Kido, Youko, Kanda, Yasuko, Taura, Naota, Ohnita, Ken, Takeshima, Fuminao, Sakai, Yusuke, Eguchi, Susumu, Nakashima, Masahiro, Nakao, Kazuhiko
Format: Article
Language:English
Subjects:
Adenosine
Analysis
Animals
Antibiotics, Antineoplastic - pharmacology
Apoptosis
Apoptosis - drug effects
Attenuation
Binding
Biology and Life Sciences
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Care and treatment
Cell death
Cells, Cultured
Cholesterol
Cytosine
Diet, High-Fat - adverse effects
Endoplasmic reticulum
Endoplasmic Reticulum Stress - drug effects
Fatty acids
Fatty liver
Fructose
Gastroenterology
Gene expression
Health aspects
Hepatocytes
Hepatocytes - cytology
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatology
Homology
Humans
In vivo methods and tests
Injury prevention
Inositol
Kinases
Lipogenesis
Liver
Liver - cytology
Liver - drug effects
Liver - metabolism
Liver cancer
Liver diseases
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Male
Medicine
Medicine and Health Sciences
Metabolic syndrome
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease - chemically induced
Non-alcoholic Fatty Liver Disease - drug therapy
Non-alcoholic Fatty Liver Disease - metabolism
Palmitic acid
Palmitic Acid - toxicity
Proteins
Pyrimidines
Rats
Rats, Wistar
Research and Analysis Methods
Rodents
Splicing
Steatosis
Stress response
Thymidine
Toyocamycin - pharmacology
Transcription factors
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Summary: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. 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. 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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0170591