CREBH knockout accelerates hepatic fibrosis in mouse models of diet-induced nonalcoholic fatty liver disease.
CREBH knockout accelerates hepatic fibrosis in mouse models of diet-induced nonalcoholic fatty liver disease.
复制标题
CREBH 敲除会加速饮食诱导的非酒精性脂肪肝小鼠模型的肝纤维化。
DOI：
10.1016/j.lfs.2020.117795
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发表时间：
2020
期刊：
影响因子：
6.1
通讯作者：
Xu Keshu
中科院分区：
文献类型：
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作者：
Li Guixin;Zhang Junli;Jiang Qianqian;Liu Beibei;Xu Keshu
目的探讨环磷酸腺苷反应元件结合蛋白H（CREBH）在非酒精性脂肪性肝病（NAFLD）发生发展中的作用。小鼠在MCD模型治疗4周和HF模型治疗24周后被处死。关键发现KO-MCD/HF组中非酒精性脂肪性肝炎相关肝纤维化的特征通过肝脏组织学分析得到验证。与WT-MCD/HF组相比，KO-MCD/HF组血浆ALT和肝羟脯氨酸水平升高。KO-MCD/HF组MCP-1、αSMA、Desmin、COL-1、TIMP-1、TGF-β1、TGF-β2表达明显升高，MMP-9和FGF 21 mRNA表达明显降低。TNFα、CTGF和CCND 1 mRNA水平在KO-HF组与对照组比较也有显著性差异。KO-MCD/HF组MCP-1、BAX、αSMA、COL-1、TGF-β1和SMAD 2/3蛋白水平显著升高，KO-HF组CCND 1蛋白水平也显著升高，提示CREBH基因敲除可能主要通过TGF-β2和FGF 21调节TGF-β1信号通路，导致NAFLD炎症和纤维化加重。
AimsThe primary focus of this study was to explore the effects of cyclic AMP response element-binding protein H (CREBH) on the development of nonalcoholic fatty liver disease (NAFLD).Materials and methodsCREBH knockout (KO) and wildtype (WT) mice were averagely divided into a methionine and choline-deficient (MCD) or high fat (HF) diet group and respective chow diet (CD) groups. Mice were sacrificed after 4-week treatment for MCD model and 24-week treatment for HF model.Key findingsCharacteristics of nonalcoholic steatohepatitis-related liver fibrosis in KO-MCD/HF group were verified by hepatic histological analyses. Compared with WT-MCD/HF group, levels of plasma ALT and hepatic hydroxyproline increased in KO-MCD/HF group. Significantly higher levels of MCP-1, αSMA, Desmin, COL-1, TIMP-1, TGF-β1, TGF-β2 were found while MMP-9 and FGF21 mRNA levels decreased in KO-MCD/HF group. There was also a distinct difference of mRNA levels of TNFα, CTGF and CCND1 in KO-HF group compared with controls. Protein levels of MCP-1, BAX, αSMA, COL-1, TGF-β1 and SMAD2/3 significantly increased in KO-MCD/HF group and CCND1 was also upregulated in KO-HF group compared to their counterparts.SignificanceCREBH knockout may primarily regulate the TGF-β1 signaling pathway via TGF-β2 and FGF21 resulting in more severe inflammation and fibrosis in NAFLD.