The Effects Of 4-phenylbutyric Acid On Carbon Tetrachloride-induced Acute Liver Injury In Mice

Objective To explore the effects and the molecular mechanisms of 4-phenylbutyric acid(PBA) on the basis of the previous model of acute liver injury in mice induced by carbon tetrachloride(CCl4), to study the effects of ERS to cell necrosis, apoptosis and proliferation of liver.Methods Sixty adult healthy male ICR mice were divided into control groups, PBA groups, CCl4 12 h groups, CCl4 24 h groups, CCl4 48 h groups, CCl4 72 h groups, PBA+CCl4 12 h groups, PBA+CCl4 24 h groups, PBA+CCl4 48 h groups, PBA+CCl4 72 h groups, each group of six mice. CCl4 groups and PBA+CCl4 groups mice were intraperitoneally(i.p.) injected with CCl4(300 ml/ kg). In PBA+CCl4 groups, mice were i. p. injected with PBA(400 mg/kg). All mice were killed to collect blood and liver specimens at different time after CCl4 treatment. Serum alanine aminotransferase(ALT) was detected. Histological examination was then performed using HE staining in light microscope and apoptosis was detected using terminal transferase d UTP nick end labeling(TUNEL). The distribution of hepatic proliferating cell nuclear antigen(PCNA) was detected by immunohistochemistry. The protein expressions of hepatic glucose-regulated protein( GRP78), C/EBP homologousprotein( CHOP) phosphorylated c-Jun N-terminal kinases(p-JNK), phosphorylated eukaryotic initiation factor 2α subunit(p-e IF2α), phosphorylated serine threonine kinase(p-akt), nuclear factor –kappa B p65(NF-κB p65), PCNA were determined using Western blot.Results Serum ALT level in PBA+CCl4 groups were reduced compared with CCl4 groups in different time-point. Liver to body weight ratio of two groups have differences only at 48 h time-point(P<0.01). PBA reduced the degree of hepaticnecrosis and apoptosis caused by CCl4 in HE. Western blot results showed that PBA reduced the liver GRP78 and others endoplasmic reticulum stress related protein levels(P<0.01). Further study found that the protein levels of p-akt, NF-κB p65 and PCNA in PBA+CCl4 groups significantly decreased(P<0.01).Conclusions Endoplasmic reticulum stress inhibitor PBA could alleviate acute hepatic necrosis and apoptosis but restrain hepatic proliferation.