Abstract
Background and aimsA 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.MethodsHuh-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.ResultsToyocamycin 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.ConclusionsThe 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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that has become a major concern worldwide
Toyocamycin reduced the expression of cytosine-cytosine-adenosine-adenosine-thymidine enhancer-binding protein homologous protein (CHOP), which is a key player in endoplasmic reticulum (ER) stress-mediated apoptosis, as well as its downstream cell death modulator, death receptor 5
Effect of toyocamycin on hepatic steatosis and liver injury liver injury caused by FFC-induced nonalcoholic fatty liver disease (NAFLD)
Summary
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that has become a major concern worldwide. Increase in the serum level of free fatty acids (FFAs) is associated with the development of NAFLD. Key transducers of the ER stress include protein kinase R-like ER kinase (PERK), serine/threonineprotein kinase endoribonuclease inositol-requiring enzyme 1 (IRE1α), and activating transcription factor 6 (ATF6), which are located in the ER lumen. JNK activation during lipoapoptosis is most likely independent of ER stress Rather, it is possibly mediated by serine/threonine kinase-, glycogen synthase kinase-3 (GSK3) beta-, and mixed-lineage kinase 3 (MLK3)-dependent mechanisms [7,8,9]. A high serum level of saturated free fatty acids (FFAs) is associated with the development of nonalcoholic fatty liver disease (NAFLD). XBP-1 is a transcription factor induced by the endoplasmic reticulum (ER) stress sensor endoribonuclease inositol-requiring enzyme 1 alpha (IRE1α). We explored the effects of toyocamycin in a mouse model of NAFLD
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