[Action mechanism of paeonol in inhibiting alcoholic liver disease through regulating PERK-eIF2α-ATF4-CHOP signaling pathway mediated by endoplasmic reticulum stress].

Aims to explore whether paeonol exerts an ameliorative effect on alcoholic liver disease(ALD) in mice by regulating protein kinase R-like endoplasmic reticulum kinase(PERK)-eukaryotic initiation factor 2α(eIF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP) signaling pathway mediated by the endoplasmic reticulum stress(ERS). Male C57BL/6J mice were randomly divided into a blank group, a model group, a paeonol group, a 4-phenylbutyric acid group, and a group with paeonol and 4-phenylbutyric acid. According to the National Institute on Alcohol Abuse and Alcoholism(NIAAA) method, the model was established by feeding the mice with the Lieber-DeCarli control liquid diet and the alcohol liquid diet. The detection indicators included serum lipids, liver function, inflammatory factors, and oxidative stress indicators; hematoxylin-eosin(HE) and oil red O staining were used to observe the pathological damage and lipid deposition of the liver; TUNEL staining was used to observe the apoptosis rate of liver cells; Western blot, immunohistochemistry, and immunofluorescence methods were used to analyze the expressions of key proteins in the PERK-eIF2α-ATF4-CHOP signaling pathway. The results show that compared with those in the blank group, the mice in the model group have significantly increased serum lipids, liver function indicators, inflammatory factors, and malondialdehyde(MDA) content(P<0.001), significantly decreased oxidative stress indicators such as the enzyme activities of superoxide dismutase(SOD) and catalase(CAT) as well as the reduced glutathione(GSH) content(P<0.001). The liver tissue have obvious infiltration in the inflammatory cells, fat vacuoles, and lipid deposition, and the apoptosis rate is significantly increased(P<0.001). The expressions of the proteins related to the ERS pathway, such as glucose regulatory protein 78(GRP78) and phosphorylation(p)-PERK, p-eIF2α, ATF4, and CHOP, are significantly increased(P<0.001). Compared with those in the model group, the related indicators are significantly reduced in the group with paeonol and 4-phenylbutyric acid; the enzyme activities of SOD and CAT as well as the level of GSH are increased(P<0.01); the inflammatory cell infiltration and lipid deposition in the liver tissue are caused by the improved alcohol liquid diet; the expressions of proteins related to the ERS pathway decrease(P<0.05). In conclusion, paeonol can effectively alleviate mice's liver injury mediated by alcohol, and its action mechanism may be related to the inhibition of the PERK-eIF2α-ATF4-CHOP signaling pathway mediated by the ERS.