Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD.
Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD.
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DOI：
10.1038/cddis.2014.162
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发表时间：
2014-04-17
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
非酒精性脂肪性肝病（NAFLD）的发病机制尚不完全清楚。在这项研究中，我们旨在评估人类和小鼠NAFLD期间肝细胞内质网应激与自噬之间的关系。将活检证实的非酒精性脂肪变性（NAS）或非酒精性脂肪性肝炎（NASH）患者的肝脏与组织学正常的肝脏进行比较，将鼠粮（CHD）小鼠的肝脏与高脂饮食（HFD）或蛋氨酸-胆碱缺乏（MCD）小鼠的肝脏进行比较，并对原代和Huh7人肝细胞进行分析棕榈酸（PA）。在NASH患者中，与NAS患者相比，内质网应激标志物（激活转录因子4 （ATF4）、葡萄糖调节蛋白78 （GRP78）和C/EBP同源蛋白（CHOP））和自噬（BCN1）的肝脏信使RNA水平显著升高。同样，与NAS患者相比，NASH患者中GRP78、CHOP和p62/SQSTM1 （p62）自噬底物的蛋白水平显著升高。在饲喂HFD或MCD的小鼠肝脏中，与冠心病小鼠相比，内质酸应激介导的信号传导与自噬通量的阻断平行，通过p62、微管相关蛋白2轻链3 (LC3-II)/LC3-I比率和自噬体积累的增加来评估。在Huh7肝细胞中，PA处理8小时可激活展开蛋白反应和自噬通量。相反，长时间使用PA（24小时）诱导内质网应激和细胞死亡，同时阻断自噬通量。在这些条件下，与雷帕霉素或CHOP沉默共同治疗可改善这些作用并减少细胞凋亡。我们的研究结果表明，NAFLD患者和小鼠模型的肝脏以及脂质超载的人肝细胞的自噬通量受损，这可能是由于内质网应激升高导致细胞凋亡。因此，旨在恢复自噬通量的治疗可能会减弱或阻止NAFLD的进展。
The pathogenic mechanisms underlying the progression of non-alcoholic fatty liver disease (NAFLD) are not fully understood. In this study, we aimed to assess the relationship between endoplasmic reticulum (ER) stress and autophagy in human and mouse hepatocytes during NAFLD. ER stress and autophagy markers were analyzed in livers from patients with biopsy-proven non-alcoholic steatosis (NAS) or non-alcoholic steatohepatitis (NASH) compared with livers from subjects with histologically normal liver, in livers from mice fed with chow diet (CHD) compared with mice fed with high fat diet (HFD) or methionine-choline-deficient (MCD) diet and in primary and Huh7 human hepatocytes loaded with palmitic acid (PA). In NASH patients, significant increases in hepatic messenger RNA levels of markers of ER stress (activating transcription factor 4 (ATF4), glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP)) and autophagy (BCN1) were found compared with NAS patients. Likewise, protein levels of GRP78, CHOP and p62/SQSTM1 (p62) autophagic substrate were significantly elevated in NASH compared with NAS patients. In livers from mice fed with HFD or MCD, ER stress-mediated signaling was parallel to the blockade of the autophagic flux assessed by increases in p62, microtubule-associated protein 2 light chain 3 (LC3-II)/LC3-I ratio and accumulation of autophagosomes compared with CHD fed mice. In Huh7 hepatic cells, treatment with PA for 8 h triggered activation of both unfolding protein response and the autophagic flux. Conversely, prolonged treatment with PA (24 h) induced ER stress and cell death together with a blockade of the autophagic flux. Under these conditions, cotreatment with rapamycin or CHOP silencing ameliorated these effects and decreased apoptosis. Our results demonstrated that the autophagic flux is impaired in the liver from both NAFLD patients and murine models of NAFLD, as well as in lipid-overloaded human hepatocytes, and it could be due to elevated ER stress leading to apoptosis. Consequently, therapies aimed to restore the autophagic flux might attenuate or prevent the progression of NAFLD.
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影响因子：
64.8
作者：
Ichimura, Y;Kirisako, T;Ohsumi, Y
通讯作者：
Ohsumi, Y
影响因子：
3.8
作者：
Lake, April D.;Novak, Petr;Cherrington, Nathan J.
通讯作者：
Cherrington, Nathan J.
影响因子：
25.7
作者：
Garcia-Monzon, Carmelo;Lo Iacono, Oreste;Martin-Sanz, Paloma
通讯作者：
Martin-Sanz, Paloma
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
4.8
作者：
Cazanave, Sophie C.;Mott, Justin L.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.