Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model.
Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model.
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DOI：
10.1016/j.toxlet.2012.02.017
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发表时间：
2012-05-20
影响因子：
3.5
通讯作者：
Zhang, Kezhong
中科院分区：
文献类型：
--
作者：
Lee, Jin-Sook;Zheng, Ze;Mendez, Roberto;Ha, Seung-Wook;Xie, Youming;Zhang, Kezhong
内质网 (ER) 应激是指未折叠或错误折叠蛋白质在 ER 腔中积累的情况，已知这种情况会激活称为未折叠蛋白质反应 (UPR) 的细胞内应激信号传导。许多药理试剂或病理生理刺激可以诱导 ER 应激和 UPR 信号激活，导致与多种疾病的发生和进展相关的细胞生理学改变。非酒精性脂肪性肝炎（NASH）以肝脏脂肪变性和炎症为特征，被认为是代谢性疾病的前兆或肝脏表现。在这项研究中，我们描述了细菌核苷抗生素衣霉素 (TM) 诱导的药理学 ER 应激在动物模型中促进 NASH 的毒性作用和分子基础。 C57BL/6J 品系背景的小鼠通过腹膜内注射 TM 来应对药理学 ER 应激。注射TM后，小鼠表现出快速的NASH状态，其特征是肝脂肪变性和炎症。在TM治疗的小鼠中观察到肝甘油三酯（TG）增加和血浆脂质减少，包括血浆TG、血浆胆固醇、高密度脂蛋白（HDL）和低密度脂蛋白（LDL）。为了应对 TM 挑战，肝脏中甾醇反应结合蛋白 (SREBP)-1a 和 SREBP-1c（脂质和甾醇生物合成的关键反式激活剂）的裂解显着增加。与肝脂肪变性表型一致，在接受TM攻击的小鼠肝脏中，一些参与从头脂肪生成和脂滴形成的关键调节因子和酶的表达上调，而参与脂肪分解和脂肪酸氧化的表达下调。此外，TM治疗显着增加NF-κB抑制剂（IκB）的磷酸化，从而激活肝脏中NF-κB介导的炎症通路。我们的研究不仅证实了药物内质网应激是引发 NASH 的强烈“打击”，而且还证明了内质网应激、脂质代谢和体内肝脏炎症之间的重要分子联系。
Endoplasmic reticulum (ER) stress refers to a condition of accumulation of unfolded or misfolded proteins in the ER lumen, which is known to activate an intracellular stress signaling termed Unfolded Protein Response (UPR). A number of pharmacologic reagents or pathophysiologic stimuli can induce ER stress and activation of the UPR signaling, leading to alteration of cell physiology that is associated with the initiation and progression of a variety of diseases. Non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis and inflammation, has been considered the precursor or the hepatic manifestation of metabolic disease. In this study, we delineated the toxic effect and molecular basis by which pharmacologic ER stress, induced by a bacterial nucleoside antibiotic tunicamycin (TM), promotes NASH in an animal model. Mice of C57BL/6J strain background were challenged with pharmacologic ER stress by intraperitoneal injection of TM. Upon TM injection, mice exhibited a quick NASH state characterized by hepatic steatosis and inflammation. An increase in hepatic triglycerides (TG) and a decrease in plasma lipids, including plasma TG, plasma cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), were observed in the TM-treated mice. In response to TM challenge, cleavage of sterol responsive binding protein (SREBP)-1a and SREBP-1c, the key trans-activators for lipid and sterol biosynthesis, was dramatically increased in the liver. Consistent with the hepatic steatosis phenotype, expression of some key regulators and enzymes in de novo lipogenesis and lipid droplet formation was up-regulated, while expression of those involved in lipolysis and fatty acid oxidation was down-regulated in the liver of mice challenged with TM. Moreover, TM treatment significantly increased phosphorylation of NF-κB inhibitors (IκB), leading to the activation of NF-κB-mediated inflammatory pathway in the liver. Our study not only confirmed that pharmacologic ER stress is a strong “hit” that triggers NASH, but also demonstrated crucial molecular links between ER stress, lipid metabolism, and inflammation in the liver in vivo.
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影响因子：
11.8
作者：
Rutkowski, D. Thomas;Wu, Jun;Back, Sung-Hoon;Callaghan, Michael U.;Ferris, Sean P.;Iqbal, Jahangir;Clark, Robert;Miao, Hongzhi;Hassler, Justin R.;Fornek, Jamie;Katze, Michael G.;Hussain, M. Mahmood;Song, Benbo;Swathirajan, Jayanth;Wang, Junying;Yau, Grace D. -Y.;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.
影响因子：
4.8
作者：
Hannah, VC;Ou, JF;Brown, MS
通讯作者：
Brown, MS
影响因子：
21.3
作者：
Feng, B;Yao, PM;Tabas, I
通讯作者：
Tabas, I
影响因子：
56.9
作者：
Lee, Ann-Hwee;Scapa, Erez F.;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
DOI：
10.1073/pnas.0808517105
发表时间：
2008-10-21
影响因子：
11.1
作者：
Bobrovnikova-Marjon, Ekaterina;Hatzivassiliou, Georgia;Diehl, J. Alan
通讯作者：
Diehl, J. Alan