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AMPK激活剂下调爆发性肝炎小鼠肝内组织因子表达

代洁, 林玲, 周丹, 艾青, 葛璞, 张力

重庆文理学院校医院，重庆 402160；重庆医科大学病理生理学教研室；生理学教研室；干细胞与组织工程研究室，重庆 400016

摘要

腺苷酸活化蛋白激酶(AMP activated protein kinase, AMPK)是重要的代谢调节酶及炎症调控新靶点。以往研究显示，AMPK激活剂5-氨基咪唑-4-甲酰胺核苷酸转甲酰酶(5-amino-4-imidazolecarboxamide riboside, AICAR)可通过抑制炎症反应减轻脂多糖/右旋半乳糖胺(lipopolysaccharide/D-galactosamine, LPS/D-gal)诱导的爆发性肝炎。由于炎症可通过激活凝血反应加重组织损伤，本研究旨在以炎症诱导凝血反应为切入点探讨AICAR保肝效应的机制。腹腔注射LPS/D-gal建立爆发性肝炎小鼠模型，用Western blot检测肝内组织因子(tissue factor, TF)、缺氧诱导因子1-α (hypoxia-inducible factor 1α, HIF-1α)以及细胞核内核因子kappa B (nuclear factor kappa B, NF-κB) p65蛋白表达，用实时定量PCR检测肝细胞促红细胞生成素(erythropoietin, EPO) mRNA表达，用试剂盒检测肝组织乳酸(lactic acid, LA)水平。结果显示，LPS/D-gal可促进小鼠肝细胞内TF蛋白表达，提高细胞核内NF-κB p65水平，上调HIF-1α蛋白及EPO mRNA表达，并提高肝组织LA水平；而AICAR干预后，以上指标均明显下调。以上结果提示，AICAR可通过抑制NF-κB活性下调TF表达及凝血活性，从而减轻肝组织缺氧及代谢紊乱，这可能是AICAR减轻LPS/D-gal诱导的爆发性肝炎的新机制。

关键词： 腺苷酸活化蛋白激酶; 组织因子 ; 凝血 ; 爆发性肝炎 ; 炎症

分类号：R966；R364.1

AMPK activator down-regulates the expression of tissue factor in fulminant hepatitis mice

DAI Jie, LIN Ling, ZHOU Dan, AI Qing, GE Pu, ZHANG Li

Hospital of Chongqing University of Arts and Sciences, Chongqing 402160, China； Department of Pathophysiology； 3Department of Physiology； 4Laboratory of Stem cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China

Abstract

AMP activated protein kinase (AMPK) is a pivotal metabolic regulatory enzyme and novel target of controlling inflammation. Our previous studies had demonstrated that 5-amino-4-imidazolecarboxamide riboside (AICAR), an AMPK activator, attenuated lipopolysaccharide (LPS)/D-galactosamine (D-gal)-induced fulminant hepatitis via suppressing inflammatory response. Since inflammation usually activates the coagulation response and aggravates inflammation-induced tissue injury, the present study was to explore the effects of AICAR on inflammation-induced activation of coagulation. Male BALB/c mice received LPS/D-gal intraperitoneal injection were used as fulminant hepatitis model. Western blot was used to detect tissue factor (TF) and hypoxia-inducible factor 1α (HIF-1α) protein expressions in hepatic tissue, as well as nuclear factor kappa B (NF-κB) p65 translocation into the nucleus. Real-time quantitative PCR was used to analyze erythropoietin (EPO) mRNA expression level. Lactic acid (LA) level in hepatic tissue was detected by kit. The results showed that LPS/D-gal induced the enhanced expression of TF, elevation of NF-κB p65 nuclear translocation, up-regulation of HIF-1α and EPO expressions, and increased LA level. These above alterations could be suppressed by AICAR. These results suggest that AICAR may down-regulate LPS/D-gal-induced TF expression (coagulation activity), and relieve hepatic hypoxia and metabolic disorder via suppressing the activity of NF-κB, which may be a novel mechanism of the beneficial effect of AICAR on LPS/D-gal-induced fulminant hepatitis.

Key words: AMP activated protein kinase; tissue factor ; coagulation ; fulminant hepatitis ; inflammation

收稿日期：2015-07-28　　录用日期：2015-10-08

通讯作者：张力　　E-mail:

引用本文：

代洁, 林玲, 周丹, 艾青, 葛璞, 张力. AMPK激活剂下调爆发性肝炎小鼠肝内组织因子表达[J]. 生理学报 2016; 68 (1): 35-40.

DAI Jie, LIN Ling, ZHOU Dan, AI Qing, GE Pu, ZHANG Li. AMPK activator down-regulates the expression of tissue factor in fulminant hepatitis mice. Acta Physiol Sin 2016; 68 (1): 35-40 (in Chinese with English abstract).