title: Decreased hepatic phosphorylated p38 mitogen-activated protein kinase contributes to attenuation of thioacetamide-induced hepatic necrosis in diet-induced obese mice.
abstract: 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.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shirai
authors.forename: Shingo
authors.initials: S
authors.lastname: Arakawa
authors.forename: Munehiro
authors.initials: M
authors.lastname: Teranishi
authors.forename: Kiyonori
authors.initials: K
authors.lastname: Kai
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D047508:Massive Hepatic Necrosis / Q000139:chemically induced* / Q000378:metabolism / Q000628:therapy*; D055432:Metabolomics; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000201:enzymology / Q000209:etiology*; D010766:Phosphorylation; D013853:Thioacetamide / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D006893:Hydroxyeicosatetraenoic Acids; D018836:Inflammation Mediators; D013853:Thioacetamide; D048051:p38 Mitogen-Activated Protein Kinases