Zhao Lei, Chen Ya-Xi, Varghese Zac, Huang Ai-Long, Tang Ren-Kuan, Jia Bei, Moorhead John F, Gong Jian-Ping, Ruan Xiong Z
Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
Lipid Research Unit, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, University College London, London, UK.
Hepatol Int. 2012 Apr;6(2):520-30. doi: 10.1007/s12072-011-9283-x. Epub 2011 Jun 24.
Murine gamma herpes virus 68 (MHV68) is a naturally occurring mouse pathogen that is homologous to Epstein-Barr virus. This study was designed to determine the correlation between MHV68 infection and lipid accumulation and insulin resistance in livers of C57BL/6J mice, and to explore the underlying mechanisms.
C57BL/6J mice fed a high fat diet were randomly assigned to receive either MHV68 or phosphate buffered saline treatment. Insulin sensitivities were evaluated by glucose tolerance tests. Serum was analyzed for lipids and cytokines. Liver was taken for histology and lipid analysis. Quantitative RT-PCR and western blotting were used to measure expression of hepatic mammalian target of rapamycin (mTOR), ribosomal S6 kinase 1 (S6K1), insulin receptor substrate-1 (IRS-1), sterol regulatory element binding protein-1 (SREBP1), fatty acid synthase (FAS), and acetyl CoA carboxylase (ACC).
MHV68 infection promoted fatty liver, hypertriglyceridemia, insulin resistance, and hyperinsulinemia in association with elevated inflammatory cytokines. In the livers of MHV68-infected C57BL/6J mice, SREBP1, FAS, ACC levels were increased. MHV68 infection also inhibited total IRS-1 expression and increased serine phosphorylation levels of IRS-1, which is parallel to the over activation of mTOR signaling pathway. Sirolimus, a specific inhibitor of mTOR pathway, inhibited MHV68-induced hepatic expression of serine p-IRS-1, increased total IRS-1 levels and improved MHV68-induced hepatic insulin resistance.
In C57BL/6J mice, MHV68 infection promotes fatty liver formation and hepatic insulin resistance, which can be ameliorated by sirolimus.
小鼠γ疱疹病毒68（MHV68）是一种与爱泼斯坦-巴尔病毒同源的天然存在的小鼠病原体。本研究旨在确定MHV68感染与C57BL/6J小鼠肝脏脂质积累和胰岛素抵抗之间的相关性，并探索其潜在机制。
将喂食高脂饮食的C57BL/6J小鼠随机分为接受MHV68或磷酸盐缓冲盐水治疗两组。通过葡萄糖耐量试验评估胰岛素敏感性。分析血清中的脂质和细胞因子。取肝脏进行组织学和脂质分析。采用定量逆转录-聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法检测肝脏中雷帕霉素靶蛋白（mTOR）、核糖体S6激酶1（S6K1）、胰岛素受体底物-1（IRS-1）、固醇调节元件结合蛋白-1（SREBP1）、脂肪酸合酶（FAS）和乙酰辅酶A羧化酶（ACC）的表达。
MHV68感染促进了脂肪肝、高甘油三酯血症、胰岛素抵抗和高胰岛素血症，并伴有炎性细胞因子升高。在感染MHV68的C57BL/6J小鼠肝脏中，SREBP1、FAS、ACC水平升高。MHV68感染还抑制了IRS-1的总表达，并增加了IRS-1的丝氨酸磷酸化水平，这与mTOR信号通路的过度激活平行。mTOR通路的特异性抑制剂西罗莫司抑制了MHV68诱导的肝脏丝氨酸磷酸化IRS-1的表达，增加了IRS-1的总水平，并改善了MHV68诱导的肝脏胰岛素抵抗。
在C57BL/6J小鼠中，MHV68感染促进脂肪肝形成和肝脏胰岛素抵抗，而西罗莫司可改善这种情况。
