Inositol-requiring enzyme 1-mediated endoplasmic reticulum stress triggers apoptosis and fibrosis formation in liver cirrhosis rat models

Abstract

Abstract. Long-term and advanced cirrhosis is usually irreversible and often coincides with variceal hemorrhage or development of hepatocellular carcinoma; therefore, liver cirrhosis is a major cause of morbidity and mortality globally. The aim of the present study was to investigate the specific mechanism behind the formation of fibrosis or cirrhosis using rat models of hepatic fibrosis. The cirrhosis model was established by intraperitoneally administering dimethylnitrosamine to the rats. Hematoxylin and eosin staining was performed on the hepatic tissues of the rats to observe the fibrosis or cirrhosis, and western blot analysis was employed to detect α-smooth muscle actin and desmin protein expression. Flow cytometric analysis was used to examine early and late apoptosis, and the protein and mRNA expression of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) pathway proteins and apoptotic proteins [C/EBP homologous protein (CHOP) and caspase-12] was detected by western blotting and the reverse-transcription polymerase chain reaction, respectively. The results indicated that the cirrhosis model was established successfully and that fibrosis was significantly increased in the cirrhosis model group compared with that in the normal control group. Flow cytometric analysis showed that early and late apoptosis in the cirrhosis model was significantly higher compared with that in the control group. The expression of the UPR pathway protein inositol-requiring enzyme (IRE) 1, as well as the expression of CHOP, was increased significantly in the cirrhotic rat tissues compared with that in the control group tissues (P<0.05). In conclusion, apoptosis was clearly observed in the hepatic tissue of cirrhotic rats, and the apoptosis was caused by activation of the ER stress-mediated IRE1 and CHOP.

Relationship analysis between gene expression profiles and rat liver cirrhosis occurrence

“…The study performed by Jiang et al (2015) showed that the levels of early, late apoptosis and cell death were significantly higher in the cirrhosis model. Accordingly, this study showed that cell death and apoptosis of hepatocytes were activated in "Diseases and Bio-functions" analysis by IPA.…”

Sanguinarine-induced apoptosis in lung adenocarcinoma cells is dependent on reactive oxygen species production and endoplasmic reticulum stress

“…The UPR attenuates ER stress by decreasing general protein translation, promoting the protein folding capacity of the ER or by enhancing ER-associated degradation (35). However, recovery from severe ER stress is difficult and it triggers apoptosis through activation of CHOP, a pro-apoptotic transcription factor involved in all three arms of UPR signaling (36)(37)(38). Many studies have found that ER stress is involved in the response of cancer cells to chemotherapeutic agents (39)(40)(41).…”

Effects of apoptosis on liver aging

“…Furthermore, ER stress involves the formation of cirrhosis. ER stress-related proteins, including inositol-requiring enzyme 1 and C/EBP homologous protein, are activated and induce apoptosis in cirrhosis[122].…”