Endoplasmic reticulum stress in liver diseases,Hepatology

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Endoplasmic reticulum stress in liver diseases
Hepatology ( IF 12.9 ) Pub Date : 2022-05-06 , DOI: 10.1002/hep.32562
Amir Ajoolabady ₁ , Neil Kaplowitz _{2,

3} , Cynthia Lebeaupin ₄ , Guido Kroemer _{5,

6,

7} , Randal J Kaufman ₄ , Harmeet Malhi ₈ , Jun Ren _{1,

9}

Affiliation

Shanghai Institute of Cardiovascular Diseases , Department of Cardiology , Zhongshan Hospital , Fudan University , Shanghai , China.
Division of Gastrointestinal and Liver Disease , Department of Medicine , Keck School of Medicine , University of Southern California , Los Angeles , California , USA.
USC Research Center for Liver Disease , Keck School of Medicine , University of Southern California , Los Angeles , California , USA.
Degenerative Diseases Program , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California , USA.
Centre de Recherche des Cordeliers , Equipe labellisée par la Ligue contre le cancer , Université de Paris , Sorbonne Université , Inserm U1138 , Institut Universitaire de France , Paris , France.
Metabolomics and Cell Biology Platforms , Institut Gustave Roussy , Villejuif , France.
Pôle de Biologie , Hôpital Européen Georges Pompidou , AP-HP , Paris , France.
Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , Minnesota , USA.
Department of Laboratory Medicine and Pathology , University of Washington , Seattle , Washington , USA.

The endoplasmic reticulum (ER) is an intracellular organelle that fosters the correct folding of linear polypeptides and proteins, a process tightly governed by the ER-resident enzymes and chaperones. Failure to shape the proper 3-dimensional architecture of proteins culminates in the accumulation of misfolded or unfolded proteins within the ER, disturbs ER homeostasis, and leads to canonically defined ER stress. Recent studies have elucidated that cellular perturbations, such as lipotoxicity, can also lead to ER stress. In response to ER stress, the unfolded protein response (UPR) is activated to reestablish ER homeostasis (“adaptive UPR”), or, conversely, to provoke cell death when ER stress is overwhelmed and sustained (“maladaptive UPR”). It is well documented that ER stress contributes to the onset and progression of multiple hepatic pathologies including NAFLD, alcohol-associated liver disease, viral hepatitis, liver ischemia, drug toxicity, and liver cancers. Here, we review key studies dealing with the emerging role of ER stress and the UPR in the pathophysiology of liver diseases from cellular, murine, and human models. Specifically, we will summarize current available knowledge on pharmacological and non-pharmacological interventions that may be used to target maladaptive UPR for the treatment of nonmalignant liver diseases.

中文翻译：

肝脏疾病中的内质网应激

内质网 (ER) 是一种细胞内细胞器，可促进线性多肽和蛋白质的正确折叠，这一过程受到 ER 驻留酶和分子伴侣的严格控制。如果未能塑造正确的蛋白质 3 维结构，最终会导致错误折叠或未折叠的蛋白质在 ER 内积累，扰乱 ER 稳态，并导致规范定义的 ER 应激。最近的研究表明，细胞扰动（例如脂毒性）也可能导致内质网应激。为了应对 ER 应激，未折叠蛋白反应 (UPR) 被激活以重建 ER 稳态（“适应性 UPR”），或者相反，当 ER 应激被压倒并持续时，会引发细胞死亡（“适应不良 UPR”）。有充分证据表明，内质网应激会导致多种肝脏病理的发生和进展，包括 NAFLD、酒精相关性肝病、病毒性肝炎、肝缺血、药物毒性和肝癌。在这里，我们回顾了细胞、小鼠和人类模型中关于 ER 应激和 UPR 在肝病病理生理学中的新作用的关键研究。具体来说，我们将总结目前有关药物和非药物干预措施的现有知识，这些干预措施可用于针对适应不良的 UPR 来治疗非恶性肝病。

更新日期：2022-05-06

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