SEC62 exacerbates hepatocyte inflammation through its involvement in autophagy regulation in a murine model of paracetamol-induced liver injury

Abstract

Abstract: Objective To investigate the mechanism of SEC62 in mice model of liver injury induced by Acetaminophen (APAP). Methods 24 mice of SPF grade C57BL/6 strain were randomly divided into blank control group (n=8), SEC62-Hepko APAP group (n=8) and SEC62-Hepflpox APAP group (n=8). Eight SEC62-Hepko and SEC62-Hepflpox mice of SPF C57BL/6 strain were injected with APAP to establish APAP Induced Liver Injury (AILI). Mice in the blank control group were injected with normal saline intraperitoneally, and the liver tissue was collected 24 hours later, and pathological, immunohistochemical staining and flow cytometry of liver tissue were performed. Results Compared with blank control group, liver pathology of mice in SEC62-Hepflpox APAP group exhibited multiple inflammatory and necrotic area of different sizes. In the SEC62-Hepko APAP group, the number and area of inflammatory necrotic lesion in liver tissue decreased. Immunohistochemical oil red staining showed that the degree of oil red staining in liver of mice in SEC62-Hepflpox APAP group was higher than that in blank control group. The degree of oil red staining in liver tissue of SEC62-Hepko APAP group decreased. Western blot analysis showed that compared with control group, the expression level of autophagy related protein P62 in liver of SEC62-Hepflpox APAP group was significantly increased (P=0.0037). The expression levels of the proteins DRP-1 and FIS-1 associated with mitochondrial cleavage and the expression level of IL-1β, a protein associated with inflammation, was significantly increased (all P<0.05). Compared with those in SEC62-Hepflpox APAP group, the expression level of autophagy related protein P62 in liver of mice in SEC62-Hepko APAP group was significantly decreased , the expression levels of the proteins DRP-1 and FIS-1 associated with mitochondrial cleavage were significantly decreased ,and the expression level of IL-1β, a protein associated with inflammation, was significantly decreased (all P<0.05). Flow cytometry showed that ROS level in liver of mice in SEC62-Hepflpox APAP group was significantly increased compared with blank control group (P<0.001). In the liver tissues of mice in SEC62-Hepko APAP group, the level of ROS in the liver of mice was significantly decreased compared with that in SEC62-Hepflpox APAP group (P<0.001). Conclusion SEC62 can affect mitochondrial homeostasis and inflammation in liver by mediating autophagy level. SEC62 knockout in hepatocytes can improve and protect the liver injury induced by APAP.

Key words: SEC62, Mitochondrial homeostasis, APAP, Inflammatory response, Drug-induced liver injury, Autophagy

LIN Jun-chao, LIU Yu-tong, ZHOU wei, JIANG Wei, HE Jie. SEC62 exacerbates hepatocyte inflammation through its involvement in autophagy regulation in a murine model of paracetamol-induced liver injury[J]. Chinese Hepatolgy, 2025, 30(8): 1151-1155.

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