天津医科大学两位教授最新成果：代谢组学的新发现

　　

天津医科大学基础医学院免疫学系姚智教授与公共卫生学院卫生毒理学教研室房中则教授最近联合报道了脂质调节NF-κB/IL-6/STAT3轴在药源性肝损伤中的作用。该研究成果2016年10月发表于毒理学领域著名杂志《Archives of Toxicology》（2015年影响因子6.637，五年平均影响因子5.574），题目为“Role of the lipid-regulated NF-κB/IL-6/STAT3 axis in alpha-naphthyl isothiocyanate-induced liver injury”。

姚智教授长期从事免疫学与疾病方面的研究，免疫毒理学中α-萘基异硫氰酸酯（ANIT）诱导的肝损伤被认为是研究药物诱导的胆汁淤积性肝炎的有用模型。房中则教授致力于毒性机制代谢组学分析，加入姚智教授博士后团队后，整合了免疫毒理学与代谢毒理学的优势，运用基于超高效液相色谱与电喷雾离子化四极杆质谱（UPLC-ESI-QTOF MS）联用的代谢组学揭示了ANIT诱导的肝损伤机制的新线索，这有助于阐明药物诱导的肝毒性。

ANIT处理的小鼠血清中LPC 18：0和LPC 18：1显著增加，这种增加是由于编码脂质代谢酶的Chka和Scd1基因改变引起的。ANIT还增强了NF-κB/IL-6/STAT3信号传导，并且体外荧光素酶受体基因试验揭示LPC18：0和LPC18：1可以浓度依赖性地激活NF-κB。从ALT和AST水平的降低和肝组织学可以看出，通过喂食小鼠Wy-14,643的饮食（0.1％）以激活PPARα可以降低ANIT诱导的肝损伤。免疫毒理学与代谢毒理学的交叉应用揭示了脂质调节NF-κB/IL-6/STAT3轴在ANIT诱导的肝脏毒性中的作用，并且表明PPARα可能是预防药物诱导的胆汁淤积性肝损伤的潜在治疗靶点。

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原文摘要：

Role of the lipid-regulated NF-κBIL-6STAT3 axis in alpha-naphthyl isothiocyanate-induced liver injury

Alpha-naphthyl isothiocyanate (ANIT)-induced liver damage is regarded as a useful model to study drug-induced cholestatic hepatitis. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOF MS)-based metabolomics revealed clues to the mechanism of ANIT-induced liver injury, which facilitates the elucidation of drug-induced liver toxicity. 1-Stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:0) and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:1) were significantly increased in serum from ANIT-treated mice, and this increase resulted from altered expression of genes encoding the lipid metabolism enzymes Chka and Scd1. ANIT also increased NF-κB/IL-6/STAT3 signaling, and in vitro luciferase reporter gene assays revealed that LPC 18:0 and LPC 18:1 can activate NF-κB in a concentration-dependent manner. Activation of PPARα through feeding mice a Wy-14,643-containing diet (0.1%) reduced ANIT-induced liver injury, as indicated by lowered ALT and AST levels, and liver histology. In conclusion, the present study demonstrated a role for the lipid-regulated NF-κB/IL-6/STAT3 axis in ANIT-induced hepatotoxicity, and that PPARα may be a potential therapeutic target for the prevention of drug-induced cholestatic liver injury.