Decreased hepatic phosphorylated p38 mitogen-activated protein kinase contributes to attenuation of thioacetamide-induced hepatic necrosis in diet-induced obese mice
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- Shirai Makoto
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
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- Arakawa Shingo
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
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- Teranishi Munehiro
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
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- Kai Kiyonori
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
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We previously reported that thioacetamide (TA)-induced hepatocellular necrosis was attenuated in mice fed a high-fat diet (HFD mice) compared with mice fed a normal rodent diet (ND mice). In this study, we investigated whether p38 mitogen-activated protein kinase (p38 MAPK) was involved in this attenuation. Western blot analysis revealed that hepatic phosphorylated p38 MAPK protein decreased at 8 and 24 hours (hr) after TA dosing in the HFD mice, while it decreased only at 24 hr in the ND mice in comparison to the time- and diet-matched, vehicle-treated mice. p38 MAPK regulates various biological functions including inflammation, therefore, hepatic metabolomics analysis focusing on pro-inflammatory lipid mediators was performed. At 24 hr after TA dosing, only one pro-inflammatory mediator, 12-hydroxyeicosatetraenoic acid (HETE), was higher in the HFD mice. On the other hand, in addition to 12-HETE, 15-HETE and 12-hydroxyeicosapentaenoic acid (HEPE) were higher and omega-3/omega-6 polyunsaturated fatty acids ratios were lower in the ND mice at 24 hr. These results of metabolomics indicated that less pro-inflammatory state was seen in HFD mice than in ND mice at 24 hr. Finally, to confirm whether the observed decrease in phosphorylated p38 MAPK could attenuate TA-induced hepatocellular necrosis, we showed that SB203580 hydrochloride, an inhibitor of p38 MAPK, partially attenuated TA-induced hepatic necrosis in ND mice. Collectively, these results suggest that a prompt decrease in phosphorylation of p38 MAPK after TA administration is one of the factors that attenuate TA-induced hepatic necrosis in HFD mice.
収録刊行物
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- The Journal of Toxicological Sciences
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The Journal of Toxicological Sciences 41 (2), 245-253, 2016
一般社団法人 日本毒性学会
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詳細情報 詳細情報について
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- CRID
- 1390282679882627456
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- NII論文ID
- 130005132658
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- NII書誌ID
- AN00002808
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- ISSN
- 18803989
- 03881350
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- NDL書誌ID
- 027267892
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- PubMed
- 26961609
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- 使用不可