Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates
Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates
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DOI：
10.1016/j.jhep.2005.10.033
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发表时间：
2006-04-01
影响因子：
25.7
通讯作者：
Hofker, MH
中科院分区：
文献类型：
--
作者：
Shiri-Sverdlov, R;Wouters, K;Hofker, MH
背景/目的：导致非酒精性脂肪性肝炎（NASH）的分子机制尚不完全清楚。在小鼠中，非诺贝特可以抑制 NASH，非诺贝特是核受体过氧化物酶体增殖物激活受体 α 的合成激动剂，可调节肝脏甘油三酯代谢。本研究旨在阐明类人高脂血症小鼠模型中 NASH 中脂肪变性和炎症之间的关系。方法：对喂食西式高脂饮食并联合或不联合非诺贝特的 APOE2 敲入小鼠的肝脏表型和基因表达进行评估。结果：为了响应西式饮食，APOE2 敲入小鼠出现了以脂肪变性和炎症为特征的 NASH。引人注目的是，在疾病进展过程中，巨噬细胞在肝脏中的积累先于脂肪变性。这种表型与基因表达模式一致，显示了两组主要基因的调节，即炎症基因和脂质基因。非诺贝特治疗减少了肝脏巨噬细胞的积累并消除了脂肪变性。此外，非诺贝特治疗后炎症基因的表达立即显着减少。结论：这些数据表明炎症可能在该小鼠模型的 NASH 发展过程中发挥重要作用。非诺贝特对 NASH 的抑制可能至少部分归因于其对促炎基因的抑制作用。 (c) 2005 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background/Aims: The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study aimed to elucidate the relation between steatosis and inflammation in NASH in a human-like hyperlipidemic mouse model.Methods: Liver phenotype and gene expression were assessed in APOE2 knock-in mice that were fed a western-type high fat diet with or without co-administration of fenofibrate.Results: In response to a western diet, APOE2 knock-in mice developed NASH characterized by steatosis and inflammation. Strikingly, macrophage accumulation in the liver preceded the steatosis during progression of the disease. This phenotype was in line with gene expression patterns, which showed regulation of two major groups of genes, i.e. inflammatory and lipid genes. Fenofibrate treatment decreased hepatic macrophage accumulation and abolished steatosis. Moreover, a marked reduction in the expression of inflammatory genes occurred immediately after fenofibrate treatment.Conclusions: These data indicate that inflammation might play an instrumental role during the development of NASH in this mouse model. Inhibition of NASH by fenofibrate may be due, at least in part, to its inhibitory effect on pro-inflammatory genes. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.