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Tumor Progression Locus 2 Depletion Inhibits Hepatic Inflammation and Steatosis and Incidence of Hepatocellular Carcinoma
Author(s) -
Li Xinli,
Liu Chun,
Stice Camilla,
Ip Blanche,
Hu KangQuan,
Greenberg Andrew,
Wang XiangDong
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.752.11
Subject(s) - steatosis , protein kinase b , medicine , hepatocellular carcinoma , endocrinology , inflammation , cancer research , phosphorylation , pi3k/akt/mtor pathway , proinflammatory cytokine , tumor progression , signal transduction , chemistry , cancer , biochemistry
Tumor progression locus 2 (TPL2) is a serine‐threonine kinase that functions as a critical regulator of inflammatory pathways and participates in oncogenic events. Non‐alcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC) development. We have recently showed that a high carbohydrates diet (HCD, 66% and 12% energy from carbohydrates and fat, respectively) induces hepatic inflammation and promotes HCC development in mice. In the present study, we investigated the role of TPL2 in the pathogenesis of HCD‐associated NAFLD and HCC in Tpl2 knock out (Tpl2 KO) mice. Both Tpl2 KO mice and wild type (WT) mice were initiated by the i.p. injection of a carcinogen (diethylnitrosamine, DEN, 25 mg/kg BW) at 2 weeks of age and followed by a HCD feeding for 22 weeks. Results showed that the deletion of Tpl2 significantly reduced hepatic inflammatory foci as compared to the WT mice. This reduction was associated with decreased phosphorylation of JNK and ERK and lower expression of hepatic inflammatory genes (IL‐1β, IL‐18, MCP‐1 and NALP3). The deletion of TPL2 also reduced steatosis which was associated with decreased hepatic expressions of ACC, SCD1, SREBP1C and AKT phosphorylation. Furthermore, the lacking of TPL2 resulted in both reduction of ER stress biomarkers and activation of mTOR signaling. Although there were no differences on tumor multiplicity and tumor volume, Tpl2 KO mice exhibited significantly lower incidence of HCC than WT mice (P<0.05). In conclusion, TPL2 plays a significant role in promoting NAFLD and the DEN‐initiated HCC development. Supported by the USDA/ARS 1950‐51000‐074S.