LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis.
LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis.
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DOI：
10.1155/2015/125380
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发表时间：
2015
影响因子：
4.6
通讯作者：
Asano T
中科院分区：
文献类型：
--
作者：
Matsunaga Y;Nakatsu Y;Fukushima T;Okubo H;Iwashita M;Sakoda H;Fujishiro M;Yamamotoya T;Kushiyama A;Takahashi S;Tsuchiya Y;Kamata H;Tokunaga F;Iwai K;Asano T
非酒精性脂肪性肝炎（NASH）是一种以肝脂质积累为特征的疾病，随后是炎症引起的肝细胞死亡和纤维化。在这一过程中，氧化应激有助于在巨噬细胞中诱导几种炎症细胞因子，包括TNF-α和il -1β，而在肝细胞中，据报道NF-κB诱导细胞存活基因的表达，以保护细胞凋亡。最近有报道称，一种新的泛素连接酶复合物称为线性泛素链组装复合物（LUBAC），由shank相关RH结构域相互作用蛋白SHARPIN、血红素氧化铁调控蛋白2泛素连接酶-1的长异构体HOIL-1L和HOIL-1L相互作用蛋白HOIP组成，在NF-κB必需调节剂（NEMO）上形成线性泛素，从而诱导NF-κB通路激活。在这项研究中，我们证明了由蛋氨酸和胆碱缺乏（MCD）饮食喂养产生的NASH啮齿动物模型肝脏中LUBAC的形成受损，首先通过凝胶过滤或Blue Native-PAGE，随后通过western blotting证实。LUBAC的减少可能是由于其成分之一SHARPIN的表达显著降低。因此，LUBAC形成受损，导致NF-κB激活不足，可能是MCD饮食诱导的NASH肝脏中肝细胞凋亡反应增强的分子机制之一。
Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic lipid accumulation followed by the inflammation-induced death of hepatocytes and fibrosis. In this process, oxidative stress contributes to the induction of several inflammatory cytokines including TNF-α andIL-1β in macrophages, while, in hepatocytes, NF-κB reportedly induces the expressions of cell survival genes for protection from apoptosis. Recently, it was reported that the new ubiquitin ligase complex termed linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on NF-κB essential modulator (NEMO) and thereby induces NF-κB pathway activation. In this study, we demonstrated the formation of LUBAC to be impaired in the livers of NASH rodent models produced by methionine and choline deficient (MCD) diet feeding, first by either gel filtration or Blue Native-PAGE, with subsequent confirmation by western blotting. The reduction of LUBAC is likely to be attributable to markedly reduced expression of SHARPIN, one of its components. Thus, impaired LUBAC formation, which would result in insufficient NF-κB activation, may be one of the molecular mechanisms underlying the enhanced apoptotic response of hepatocytes in MCD diet-induced NASH livers.
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影响因子：
13.5
作者：
Miura, Kouichi;Yang, Ling;van Rooijen, Nico;Brenner, David A.;Ohnishi, Hirohide;Seki, Ekihiro
通讯作者：
Seki, Ekihiro
影响因子：
5
作者：
Seymour, R. E.;Hasham, M. G.;Sundberg, J. P.
通讯作者：
Sundberg, J. P.
影响因子：
50.3
作者：
Luedde, Tom;Beraza, Naiara;Pasparakis, Manolis
通讯作者：
Pasparakis, Manolis
影响因子：
3.7
作者：
Sieber S;Lange N;Kollmorgen G;Erhardt A;Quaas A;Gontarewicz A;Sass G;Tiegs G;Kreienkamp HJ
通讯作者：
Kreienkamp HJ
影响因子：
64.8
作者：
Ikeda, Fumiyo;Deribe, Yonathan Lissanu;Skanland, Sigrid S.;Stieglitz, Benjamin;Grabbe, Caroline;Franz-Wachtel, Mirita;van Wijk, Sjoerd J. L.;Goswami, Panchali;Nagy, Vanja;Terzic, Janos;Tokunaga, Fuminori;Androulidaki, Ariadne;Nakagawa, Tomoko;Pasparakis, Manolis;Iwai, Kazuhiro;Sundberg, John P.;Schaefer, Liliana;Rittinger, Katrin;Macek, Boris;Dikic, Ivan
通讯作者：
Dikic, Ivan