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

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, Kazuwa

doi:10.1371/journal.pone.0170591

Cited by 37 publications

(26 citation statements)

References 40 publications

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“…In addition, endoplasmic reticulum (ER) stress and mitochondrial dysfunction ultimately lead to apoptosis of hepatic cells, which is known as NASH [ 26 ]. As shown in our results, treatment with 300 μ M PA caused prominent apoptotic death of HepG2 cells, as had already been reported by others [ 27 ]. As expected, we found that ACE had statistically significant anti-NASH effects ( Figure 3 ).…”

Section: Discussionsupporting

confidence: 92%

Artemisia iwayomogi plus Curcuma longa Synergistically Ameliorates Nonalcoholic Steatohepatitis in HepG2 Cells

Kim

Lee

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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The combination of Artemisia iwayomogi and Curcuma longa radix is frequently prescribed for liver diseases in TKM. However, the synergic effects of the two herbs on nonalcoholic steatohepatitis (NASH) have not yet been studied. Therefore, we investigated the anti-NASH effects of the water extract of A. iwayomogi (AI), C. longa radix (CL), and combination of the two herbs (ACE). Hepatic steatosis and NASH were induced in HepG2 cells by treatment with palmitic acid (PA, for 6 h) with/without pretreatment of ACE (25 or 50 μg/mL), AI (50 or 100 μg/mL), CL (50 or 100 μg/mL), curcumin (5 μg/mL), or scopoletin (5 μg/mL). The PA treatment (200 μM) drastically altered intracellular triglyceride levels, total cholesterol, and expression levels of genes related to lipid metabolism (CD36, SREBP1c, PPAR-γ, and PPAR-α), whereas pretreatment with ACE significantly attenuated these alterations. ACE also protected HepG2 cells from PA- (300 μM-) induced endoplasmic reticulum (ER) stress and apoptosis and attenuated the related key molecules including GRP78, eIF2, and CHOP, respectively. In conclusion, we found synergic effects of A. iwayomogi and C. longa on NASH, supporting the clinical potential for fatty liver disorders. In addition, modulation of ER stress-relative molecules would be involved in its underlying mechanism.

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Section: Discussionsupporting

confidence: 92%

Artemisia iwayomogi plus Curcuma longa Synergistically Ameliorates Nonalcoholic Steatohepatitis in HepG2 Cells

Kim

Lee

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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“…**P < 0.01, ***P < 0.001 versus the control group; ##P < 0.01, ###P < 0.001 versus the HFD group. accumulation under the HFD and obesity conditions, leading to lipotoxic liver injury, which activates endoplasmic reticulum (ER) stress and mitochondrial dysfunction-dependent apoptotic signaling, resulting in hepatic apoptosis (29,30). In the present study, our data showed that HFD induced marked hepatic fat accumulation, augmented apoptosis-related protein levels and the percentages of hepatocytes undergoing apoptosis, indicating the occurrence of hepatic lipoapoptosis.…”

Section: Discussionsupporting

confidence: 51%

Purple sweet potato color protects against hepatocyte apoptosis through Sirt1 activation in high-fat-diet-treated mice

Su¹,

Zhang²,

Chen³

et al. 2020

Food & Nutrition Research

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Background: Recent evidence indicates that the inhibition of hepatocyte apoptosis is possible to develop a potential therapeutic strategy for nonalcoholic fatty liver disease (NAFLD). Our previous work suggested that purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, effectively improved many features of high-fat diet (HFD)-induced NAFLD. However, whether PSPC ameliorates HFD-induced hepatocyte apoptosis has never been investigated. Objective: Here we investigated the effects of PSPC on HFD-induced hepatic apoptosis and the mechanisms underlying these effects. Design: Mice were divided into four groups: Control group, HFD group, HFD + PSPC group and PSPC group. PSPC was administered by daily oral gavage at doses of 700 mg/kg/day for 20 weeks. EX-527 (a SirT1-selective inhibitor) and Sirt1 siRNA were used to demonstrate the Sirt1 dependence of PSPC-mediated effects on apoptotic and survival signaling pathways in vivo and in vitro. Results: Our results showed that PSPC reduced body weights, hepatic triglyceride contents, histopathological lesions and serum ALT levels in a mouse model of NAFLD induced by HFD. Furthermore, PSPC attenuated HFD-induced hepatocyte apoptosis ratio from 7.27 ± 0.92% to 1.79 ± 0.27% in mouse livers, which is insignificant compared with that of controls. Moreover, PSPC activated Sirt1 by boosting NAD + level in HFD-treated mouse livers. Furthermore, PSPC promoted Sirt1-dependent suppression of P53-mediated apoptotic signaling and activation of Akt survival signaling pathway in HFD-treated mouse livers, which was confirmed by EX527 treatment. Moreover, Sirt1 knockdown abolished these ameliorative effects of PSPC on apoptosis and P53 acetylation and protein expression in PA-treated L02 cells. Ultimately, PSPC reduced Caspase-3 activation and Bax level, and elevated the Bcl-2 level in HFD-treated mouse livers. Conclusion: PSPC protected against HFD-induced hepatic apoptosis by promoting Sirt1-dependent inhibition of p53-apoptotic pathway and facilitation of Akt survival pathway. This study indicates that PSPC is a candidate for nutritional intervention of NAFLD.

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“…With respect to the anti-tumor functions of toyocamycin, some reports noted that toyocamycin inhibited XBP1 splicing via a conformational change in IRE1α to attenuate the activation of XBP1 [ 20 , 45 ]. One study reported that toyocamycin did not cause IRE1α phosphorylation, but specifically blocked its endoribonuclease activity [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing’s sarcoma

et al. 2018

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Ewing's sarcoma (ES) is the second-most frequent pediatric bone tumor. Chromosomal translocation t(11;22)(q24:q12) results in the formation of EWS/FLI1 gene fusion, which is detected in approximately 90% of tumors of the Ewing family. Several transcriptome studies have provided lists of genes associated with EWS/FLI1 expression. However, the protein expression profiles associated with EWS/FLI1 have yet to be elucidated. In this study, to identify the regulated proteins associated with EWS/FLI1 and therapeutic targets in ES, we conducted proteomic studies using EWS/FLI1 knockdown in four Ewing's sarcoma cell lines and human mesenchymal stem cells (hMSCs) expressing EWS/FLI1. Isobaric tags for relative and absolute quantitation (i-TRAQ) analyses identified more than 2,000 proteins regulated by the EWS/FLI1 fusion. In addition, the network analyses identified several critical pathways, including XBP1, which was ranked the highest. XBP1 is a protein well known to play an important role in the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress through the IRE1α-XBP1 pathway. We confirmed the high mRNA expression of XBP1 (spliced XBP1 and unspliced XBPl) in surgical samples and cell lines in ES. The silencing of XBP1 significantly suppressed the cell viabilities in ES cell lines. In the inhibitor assays using IRE1α-XBP1 inhibitors, including toyocamycin, we confirmed that these agents significantly suppressed the cell viabilities, leading to apoptosis in ES cells both in vitro and in vivo. Our findings suggested that IRE1α-XBP1 inhibitors might be useful for developing novel therapeutic strategies in ES.

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

Cited by 37 publications

References 40 publications

Artemisia iwayomogi plus Curcuma longa Synergistically Ameliorates Nonalcoholic Steatohepatitis in HepG2 Cells

Artemisia iwayomogi plus Curcuma longa Synergistically Ameliorates Nonalcoholic Steatohepatitis in HepG2 Cells

Purple sweet potato color protects against hepatocyte apoptosis through Sirt1 activation in high-fat-diet-treated mice

IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing’s sarcoma

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