罗格列酮通过抑制多条内质网应激通路保护对乙酰氨基酚诱导的急性肝损伤。
Rosiglitazone Protects against Acetaminophen-Induced Acute Liver Injury by Inhibiting Multiple Endoplasmic Reticulum Stress Pathways.
机构信息
College of Medicine, Anhui University of Science and Technology, Huainan 232001, China.
Anhui No.2 Provincial People's Hospital, Hefei 230041, China.
出版信息
Biomed Res Int. 2022 Dec 21;2022:6098592. doi: 10.1155/2022/6098592. eCollection 2022.
BACKGROUND
Excessive acetaminophen (APAP) use can lead to acute liver injury (ALI) by inducing endoplasmic reticulum stress (ERS). We previously found that pretreatment with the peroxisome proliferator-activated receptor- (PPAR-) ligand rosiglitazone (RSG) alleviated ALI in APAP-treated mice.
OBJECTIVE
To examine if RSG-mediated hepatoprotection is associated with ERS suppression.
METHODS
Forty-eight male CD-1 mice were randomly divided into control, RSG, APAP 4 h, APAP 24 h, RSG + APAP 4 h, and RSG + APAP 24 h groups. The RSG and RSG + APAP groups received RSG (20 mg/kg) by gavage 48, 24, and 1 h before intraperitoneal injection of 300 mg/kg APAP, while the APAP group received APAP alone and the control group received only normal saline. Animals were sacrificed immediately (RSG and control groups), 4 h (APAP 4 h and RSG + APAP 4 h), or 24 h (APAP 24 h and RSG + APAP 24 h) post-APAP injection. Liver tissues were collected for hematoxylin-eosin staining, TUNEL staining, and Western blotting for ERS-associated proteins. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were also measured. A second cohort received APAP or RSG + APAP as described and were monitored for survival over one week.
RESULTS
At 4 and 24 h following APAP injection alone, serum ALT and AST levels were significantly elevated, and central lobular necrosis of the liver was observed. Necrosis area reached 21.7% at 4 h and 32.1% at 24 h post-APAP, while apoptotic fractions reached 25.6% and 32.4%. Further, 50% of mice in the survival analysis cohort died within one week post-APAP. At 4 h post-APAP, the ERS marker glucose-regulated protein-78 (GRP78) and ERS-associated proteins pJNK, GRP78, p-eIF2, pPERK, and pIRE were all significantly upregulated. Pretreatment with RSG significantly reduced serum ALT and AST, liver necrosis area, apoptosis rate, and expression of ERS-associated proteins compared to APAP alone, while increasing survival to 80%.
CONCLUSIONS
Rosiglitazone pretreatment can alleviate APAP-induced ALI by suppressing three branches of ERS signaling.
背景
过量使用对乙酰氨基酚（APAP）会通过诱导内质网应激（ERS）导致急性肝损伤（ALI）。我们之前发现，过氧化物酶体增殖物激活受体-（PPAR-）配体罗格列酮（RSG）预处理可减轻 APAP 处理的小鼠的 ALI。
目的
研究 RSG 介导的肝保护作用是否与 ERS 抑制有关。
方法
48 只雄性 CD-1 小鼠随机分为对照组、RSG 组、APAP 4 小时组、APAP 24 小时组、RSG+APAP 4 小时组和 RSG+APAP 24 小时组。RSG 和 RSG+APAP 组分别在腹腔注射 300mg/kg APAP 前 48、24 和 1 小时给予 RSG（20mg/kg）灌胃，APAP 组给予 APAP 单独，对照组给予生理盐水。动物在（RSG 和对照组）、4 小时（APAP 4 小时和 RSG+APAP 4 小时）或 24 小时（APAP 24 小时和 RSG+APAP 24 小时）后立即处死注射 APAP。收集肝组织进行苏木精-伊红染色、TUNEL 染色和 Western blot 检测 ERS 相关蛋白。还测量了血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平。第二组接受了如前所述的 APAP 或 RSG+APAP 处理，并在一周内监测存活情况。
结果
APAP 单独注射后 4 和 24 小时，血清 ALT 和 AST 水平明显升高，并观察到肝中央小叶坏死。坏死面积在 4 小时时达到 21.7%，在 24 小时时达到 32.1%，而凋亡分数分别达到 25.6%和 32.4%。此外，生存分析队列中有 50%的小鼠在 APAP 后一周内死亡。APAP 后 4 小时，ERS 标志物葡萄糖调节蛋白 78（GRP78）和 ERS 相关蛋白 pJNK、GRP78、p-eIF2、pPERK 和 pIRE 均明显上调。与 APAP 单独处理相比，RSG 预处理可显著降低血清 ALT 和 AST、肝坏死面积、凋亡率和 ERS 相关蛋白的表达，并将存活率提高至 80%。
结论
RSG 预处理可通过抑制 ERS 信号的三个分支来减轻 APAP 诱导的 ALI。
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