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

Date Published: March 9, 2017

Publisher: Public Library of Science

Author(s): Ikuko Takahara, Yuko Akazawa, Maiko Tabuchi, Katsuya Matsuda, Hisamitsu Miyaaki, Youko Kido, Yasuko Kanda, Naota Taura, Ken Ohnita, Fuminao Takeshima, Yusuke Sakai, Susumu Eguchi, Masahiro Nakashima, Kazuhiko Nakao, Salvatore Papa.


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.

Partial Text

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that has become a major concern worldwide. NAFLD is a hepatic manifestation of metabolic syndrome and includes liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with liver dysfunction [1]. Long-term follow-up studies in patients with NAFLD suggest that, once NASH develops, it causes cirrhosis and can lead to end-stage liver disease or hepatocellular carcinoma [2]. However, currently, there is no available standard pharmacotherapy for NAFLD.

The major findings of this study were as follows. Toyocamycin suppressed FFA-induced apoptotic pathways as well as steatosis in the cultured hepatocytes. It also decreased serum liver dysfunction indicators and the serum levels of total cholesterol and TG in the FFC-fed mice. Lastly, it decreased steatosis and the expression of lipogenic genes in the FFC-fed mice.




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