COX-2/sEH双抑制剂PTUPB抑制肝星型细胞活化减轻小鼠肝纤维化

doi:10.13418/j.issn.1001-165x.2023.1.11

Abstract

Abstract: Objective To investigate the role of arachidonic acid (ARA) in liver fibrosis associated with non-alcoholic fatty liver disease (NAFLD) through cytochrome P450 (CYPs) and cyclooxygenase-2 (COX-2) metabolic pathways, and to explore the mechanism from the perspective of activation of hepatic astrocytes (HSC). Methods Male C57BL/6J mice were used as research subjects, and the mice model of NAFLD-related liver fibrosis was induced by high sugar and high-fat feeding (HFD). Mice were given a daily subcutaneous injection of COX-2/soluble epoxide hydrolase (sEH) dual inhibitor PTUPB (5 mg/kg). After 12 weeks, the effect of COX-2/sEH double inhibition on NAFLD-related liver fibrosis in mice was observed. The bodyweight of mice was recorded. Glucose tolerance of mice was detected. HE staining was used to observe pathological damage of liver tissue, and oil red O staining was used to observe lipid accumulation in liver tissue of mice. Masson staining and Western blot were used to detect collagen content in liver tissue. The expression of matrix metalloproteinase-inhibitor-related genes in mouse liver tissue was detected by Real- time PCR. Western blot was used to detect the effect of PTUPB on the activation of JS1 induced by palmitic acid (PA). Results PTUPB could significantly reduce the bodyweight of HFD mice, improve the glucose tolerance of mice, reduce the pathological damage of liver tissue, lipid accumulation, and collagen deposition. PTUPB could also decrease the expression of matrix metalloproteinase inhibitors Timp1 mRNA and Timp2 mRNA in liver tissues of HFD mice. PTUPB was observed to reduce PA-induced activation of JS1 cells at the cellular level. Conclusions Inhibition of ARA COX-2 /sEH metabolism can reduce HFD-induced NAFLD-related liver fibrosis in mice, and the mechanism is related to inhibition of HSC activation.

Key words: NAFLD; , , Liver fibrosis; , , COX-2/sEH dual inhibitor; , , Hepatic astrocyte

CLC Number:

R333.4

Ma Ling, Hong Jieru, Jin Ling, Liu Yubiao, Yang Jintong, Zhou Yong, Zhang Chenyu. COX-2 /sEH dual inhibitor PTUPB alleviates liver fibrosis in mice by inhibiting activation of hepatic astrocytes[J]. Chinese Journal of Clinical Anatomy, 2023, 41(1): 58-63.

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COX-2 /sEH dual inhibitor PTUPB alleviates liver fibrosis in mice by inhibiting activation of hepatic astrocytes

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