Rosiglitazone Protects against Acetaminophen‐Induced Acute Liver Injury by Inhibiting Multiple Endoplasmic Reticulum Stress Pathways

Abstract

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-γ (PPAR-γ) 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-eIF2α, 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.

A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin‐induced hepatotoxicity in mice

“…Moreover, evidence has suggested that activation of ERS and apoptosis could cause liver injury, 42 which is consistent with our previous findings in LO2 cells after CTD intervention 8 . Furthermore, suppressing three branches of the ERS signalling pathway could alleviate DILI 43 …”

“…8 Furthermore, suppressing three branches of the ERS signalling pathway could alleviate DILI. 43 To further explore the upstream pathway of apoptosis, the related proteins with ERS including GRP78, PERK, IRE1α, ATF6, ATF4 and CHOP were detected by Western blotting. Our results showed that the administration of CTD could significantly enhance the protein expressions of GRP78, PERK, IRE1α, ATF6, ATF4 and CHOP in mice, indicating that CTD induced ERS response.…”

Geometric Isomer of Guanabenz Confers Hepatoprotection to a Murine Model of Acetaminophen Toxicity

“…Treatment with Z-GA resulted in the accumulation of the phosphorylated eIF2α protein, thus relieving the ER stress by attenuation of new protein synthesis. Increased expression of p-eIF2α has been noted in other studies investigating APAP-induced ER stress, − which could stem from differences in exposure time and the animal model used. However, the inhibition of eIF2α dephosphorylation caused by Z -GA is hepatoprotective, suggesting an important role for the PERK pathway in APAP toxicity.…”