Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice
Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice
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DOI：
10.1152/ajpgi.00163.2009
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发表时间：
2011-03-01
影响因子：
4.5
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
--
作者：
Csak, Timea;Velayudham, Arumugam;Szabo, Gyongyi
[10]李文，李文.髓样分化因子-2和toll样受体4表达缺陷可减轻小鼠非酒精性脂肪性肝炎和纤维化美国生理学杂志胃肠和肝脏生理学300：G433-G441，2011年。首次发表于2011年1月13日; doi：10.1152/ajpgi.00163.2009.- Toll样受体4（TLR 4）及其辅助受体髓样分化因子-2（MD-2）在识别脂多糖（LPS）和激活促炎通路中起关键作用。在这里，我们测试了TLR 4及其辅助受体MD-2在非酒精性脂肪性肝炎（NASH）和非酒精性脂肪性肝病的肝纤维化中发挥核心作用的假设。对照基因型小鼠和MD-2或TLR 4缺陷[敲除（KO）]小鼠接受甲硫氨酸胆碱缺陷（MCD）或甲硫氨酸胆碱补充（MCS）饮食。在对照基因型小鼠中，与MCS饲料相比，MCD饲料导致NASH、肝脏甘油三酯蓄积和硫代巴比妥酸反应性物质（脂质过氧化的标志物）增加。NASH的这些特征在MD-2 KO和TLR 4 KO小鼠中显著减弱。在喂食MCD饲料的基因型对照组中，血清丙氨酸转氨酶（肝损伤的指标）升高，但在MD-2 KO和TLR 4 KO小鼠中减弱。与相应基因型对照小鼠相比，喂食MCD饲料的MD-2 KO和TLR 4 KO小鼠的炎症激活（通过血清TNF-α和烟酰胺腺嘌呤二核苷酸磷酸氧化酶复合物mRNA表达和激活表示）显著较低。与对照基因型相比，MD-2和TLR 4 KO中的肝纤维化标志物[天狼星红和α-平滑肌肌动蛋白（SMA）染色的胶原蛋白、前胶原蛋白-I、转化生长因子-β 1、α-SMA、基质金属蛋白酶-2和基质金属蛋白酶组织抑制剂-1 mRNA]减弱。总之，我们的研究结果表明，LPS识别复合物，包括MD-2和TLR 4，通过NADPH活化在小鼠肝脏脂肪变性和NASH模型中的纤维化中的新的，关键的作用。
Csak T, Velayudham A, Hritz I, Petrasek J, Levin I, Lippai D, Catalano D, Mandrekar P, Dolganiuc A, Kurt-Jones E, Szabo G. Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol 300: G433-G441, 2011. First published January 13, 2011; doi:10.1152/ajpgi.00163.2009.-Toll-like receptor 4 (TLR4) and its coreceptor, myeloid differentiation factor-2 (MD-2), are key in recognition of lipopolysaccharide (LPS) and activation of proinflammatory pathways. Here we tested the hypothesis that TLR4 and its coreceptor MD-2 play a central role in nonalcoholic steatohepatitis (NASH) and liver fibrosis in nonalcoholic fatty liver disease. Mice of control genotypes and those deficient in MD-2 or TLR4 [knockout (KO)] received methionine choline-deficient (MCD) or methionine choline-supplemented (MCS) diet. In mice of control genotypes, MCD diet resulted in NASH, liver triglycerides accumulation, and increased thiobarbituric acid reactive substances, a marker of lipid peroxidation, compared with MCS diet. These features of NASH were significantly attenuated in MD-2 KO and TLR4 KO mice. Serum alanine aminotransferase, an indicator of liver injury, was increased in MCD diet-fed genotype controls but was attenuated in MD-2 KO and TLR4 KO mice. Inflammatory activation, indicated by serum TNF-alpha and nictoinamide adenine dinucleotide phosphate oxidase complex mRNA expression and activation, was significantly lower in MCD diet-fed MD-2 KO and TLR4 KO compared with corresponding genotype control mice. Markers of liver fibrosis [collagen by Sirius red and alpha-smooth muscle actin (SMA) staining, procollagen-I, transforming growth factor-beta 1, alpha-SMA, matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-1 mRNA] were attenuated in MD-2 and TLR4 KO compared with their control genotype counterparts. In conclusion, our results demonstrate a novel, critical role for LPS recognition complex, including MD-2 and TLR4, through NADPH activation in liver steatosis, and fibrosis in a NASH model in mice.