Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, Iowa.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
Semin Liver Dis. 2023 Aug;43(3):279-292. doi: 10.1055/a-2129-8977. Epub 2023 Jul 14.
Exposure to hepatotoxic chemicals is involved in liver disease-related morbidity and mortality worldwide. The liver responds to damage by triggering compensatory hepatic regeneration. Physical agent or chemical-induced liver damage disrupts hepatocyte proteostasis, including endoplasmic reticulum (ER) homeostasis. Post-liver injury ER experiences a homeostatic imbalance, followed by active ER stress response signaling. Activated ER stress response causes selective upregulation of stress response genes and downregulation of many hepatocyte genes. Acetaminophen overdose, carbon tetrachloride, acute and chronic alcohol exposure, and physical injury activate the ER stress response, but details about the cellular consequences of the ER stress response on liver regeneration remain unclear. The current data indicate that inhibiting the ER stress response after partial hepatectomy-induced liver damage promotes liver regeneration, whereas inhibiting the ER stress response after chemical-induced hepatotoxicity impairs liver regeneration. This review summarizes key findings and emphasizes the knowledge gaps in the role of ER stress in injury and regeneration.
暴露于肝毒性化学物质与全球范围内与肝病相关的发病率和死亡率有关。肝脏通过触发代偿性肝再生来对损伤做出反应。物理因子或化学诱导的肝损伤破坏了肝细胞的蛋白质稳态，包括内质网（ER）稳态。肝损伤后，ER 经历了一个平衡失调，随后 ER 应激反应信号被激活。激活的 ER 应激反应导致应激反应基因的选择性上调和许多肝细胞基因的下调。对乙酰氨基酚过量、四氯化碳、急性和慢性酒精暴露以及物理损伤会激活 ER 应激反应，但 ER 应激反应对肝再生的细胞后果的详细信息仍不清楚。目前的数据表明，在部分肝切除诱导的肝损伤后抑制 ER 应激反应会促进肝再生，而在化学诱导的肝毒性后抑制 ER 应激反应会损害肝再生。本综述总结了关键发现，并强调了 ER 应激在损伤和再生中的作用方面的知识空白。
