Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet
Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet
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DOI：
10.1152/ajpgi.00132.2015
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发表时间：
2015-12-15
影响因子：
4.5
通讯作者：
Green, Richard M.
中科院分区：
文献类型：
--
作者：
Liu, Xiaoying;Henkel, Anne S.;Green, Richard M.
脂肪肝与内质网应激和肝脏未折叠蛋白反应（UPR）的激活有关。UPR调节因子X-box结合蛋白1剪接（XBP1s）的肝脏表达减少与人类非酒精性脂肪性肝炎（NASH）有关，给小鼠喂食含有果糖/蔗糖的高脂肪饮食会导致进行性纤维化脂肪性肝炎。本研究探讨了XBP1在非酒精性脂肪肝损伤和脂肪酸诱导的细胞损伤中的作用。肝细胞特异性Xbp1缺陷（Xbp1(-/-)）小鼠被喂食高脂/糖（HFS）饮食长达16周。hfs喂养的Xbp1（-/-）小鼠与Xbp1（-/-）对照组相比，血清丙氨酸转氨酶水平更高。hfs喂养的Xbp1（-/-）小鼠肝脏mRNA的RNA测序和基因发生通路分析显示，凋亡过程、炎症反应和细胞外基质结构成分通路的激活增强。hfs喂养的Xbp1（-/-）小鼠肝脏组织学显示损伤和纤维化增强，但脂肪变性减少。HFS喂养后，与Xbp1（-/-）小鼠相比，Xbp1（-/-）小鼠的肝脏Col1a1和Tgf β 1基因表达以及Chop和磷酸化JNK （p-JNK）均升高。在体外，生成稳定的xbp1敲低Huh7细胞（Huh7- kd）和scramble对照细胞（Huh7- scr），并用棕榈酸（PA）处理24小时。通过乳酸脱氢酶释放、凋亡核和caspase3/7活性测定，与Huh7- scr细胞相比，PA处理的Huh7- kd细胞具有更高的细胞毒性。PA处理后，Huh7-KD细胞中CHOP和p-JNK的表达也增加。综上所述，在体内和体外脂肪肝损伤模型中，XBP1的缺失均增强了损伤。我们推测肝脏XBP1在NASH发病机制中起重要的保护作用。
Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient (Xbp1(-/-)) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1(-/-) mice exhibited higher serum alanine aminotransferase levels compared with Xbp1(-/-) controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1(-/-) mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1(-/-) mice. Hepatic Col1a1 and Tgf beta 1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1(-/-) compared with Xbp1(-/-) mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.