ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets.
ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets.
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DOI：
10.3389/fmolb.2021.804097
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发表时间：
2021
影响因子：
5
通讯作者：
Maiers JL
中科院分区：
文献类型：
--
作者：
Duwaerts CC;Maiers JL
内质网在肝脏病理生理学中起着核心作用。通过脂质含量增加、酒精代谢或错误折叠蛋白的积累对内质网造成的慢性损伤，会引发内质网应激、肝细胞功能失调、炎症以及疾病发病机制的恶化。内质网应对并解除应激的一个关键适应性反应是清除过量或错误折叠的蛋白质。内质网腔内或内质网膜蛋白的降解通过不同机制发生，其中包括内质网相关降解（ERAD）以及内质网与溶酶体相关的降解（ERLAD），后者涵盖巨自噬性内质网自噬、微自噬性内质网自噬以及依赖Atg8/LC - 3的囊泡运输。这三个过程对于清除错误折叠或未折叠的蛋白质聚集体，以及在内质网扩张/应激后重新建立内质网稳态至关重要，而内质网稳态对于肝脏功能以及肝脏对损伤的适应能力至关重要。尽管这些降解过程在解除内质网应激中发挥关键作用，但它们对肝脏生理和病理生理学的贡献却研究不足。对来自患病肝脏的公开可用数据集的分析显示，许多参与内质网相关降解途径的基因表达失调；然而，它们在疾病进展中的作用和调控机制尚不明确。在此，我们将探讨慢性肝病中内质网相关蛋白质清除途径的动态调控、细胞类型特异性作用，以及治疗慢性肝病的潜在可靶向机制。
The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.
影响因子：
3.6
作者：
Masouminia, M.;Samadzadeh, S.;Ebaee, A.;French, B. A.;Tillman, B.;French, S. W.
通讯作者：
French, S. W.