Role and mechanism of action of endoplasmic reticulum stress in the formation of sex difference in liver diseases / 临床肝胆病杂志

ABSTRACT

ObjectiveTo investigate the role and mechanism of endoplasmic reticulum stress in the formation of sex difference in liver diseases. MethodsA retrospective analysis was performed to investigate the sex distribution of 23 043 patients with liver diseases in the outpatient service of hepatology and 1110 patients with liver diseases in Department of Hepatology in Zunyi Medical University in 2018. A mouse model of acute liver injury was established by intraperitoneal injection of carbon tetrachloride to confirm the sex difference of liver injury and investigate the mechanism of action of endoplasmic reticulum stress in the formation of sex difference in liver injury. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. The chi-square test was used for comparison of categorical data. ResultsAmong the patients in the outpatient service and the hospitalized patients, the male patients had a significantly higher incidence rate than the female patients, with a male/female ratio of 1.56∶1 in the patients in the outpatient service and 1.86∶1 in the hospitalized patients, and there was a significant difference between the two groups of patients (χ2=7.517, P=0.003). The animal model study showed that compared with the female mice with acute liver injury induced by carbon tetrachloride, the male mice had significantly higher death rate (50% vs 30%, P＜0.05), serum levels of alanine aminotransferase (5767.8±518.8 U/L vs 4749.5±378.0 U/L, P＜0.05) and total bilirubin (6.20±0.88 mmol/L vs 4.83±0.57 mmol/L, P＜0.05), liver necrotic area (47.50%±4.65% vs 38.80%±5.00%, P=0.043), and protein expression of the marker for hepatocyte apoptosis clea-caspase-3 (26.00±2.11 vs 18.40±1.54, P=0.042). Compared with the control mice, the model mice had significant increases in the expression of p-PERK, XBP1s, P58IPK, and CHOP in the liver (all P＜0.05). Compared with the female model mice, the male model mice had significantly higher expression of XBP1s (25.92±2.11 vs 15.54±1.21, P=0.033), P58IPK (28.60±2.43 vs 13.56±1.13, P=0.026), and CHOP (27.15±2.61 vs 18.18±1.81, P=0.038) and significantly lower expression of p-PERK (16.82±0.11 vs 22.84±0.03, P=0.043) in the liver. Immunohistochemistry also showed that the male mice had significantly higher expression of CHOP than the female mice (1.00±0.11 vs 0.62±0.03, P=0.032). ConclusionThe uncoordinated activation of the endoplasmic reticulum stress signaling pathway may be involved in the formation of sex difference in liver diseases.