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

目的 探讨花生四烯酸（ARA）经细胞色素P450(CYPs)及环氧合酶2(COX-2)代谢途径在非酒精性脂肪肝（NAFLD）相关肝纤维化中的作用，并从肝星形细胞（HSC）活化的角度探讨其机制。方法采用雄性C57BL/6J小鼠为研究对象，高糖高脂饲养（HFD）诱导小鼠NAFLD相关肝纤维化模型。给予小鼠每天皮下注射COX-2/可溶性环氧化物水解酶（sEH）双抑制剂PTUPB(5 mg/kg)。12周后观察COX-2/sEH双抑制对小鼠NAFLD相关肝纤维化的影响。记录小鼠体重变化；检测小鼠葡萄糖耐受性；HE染色观察小鼠肝组织病理损伤；油红O染色观察小鼠肝组织脂质堆积；Masson染色及Western blot法检测肝组织胶原含量；Real-time PCR法检测小鼠肝组织基质金属蛋白酶抑制因子相关基因表达；Western blot法检测PTUPB对棕榈酸（PA）诱导的肝星形细胞JS1活化的影响。结果 PTUPB可显著降低HFD小鼠的体重，提高小鼠葡萄糖耐受性，减轻肝组织病理损伤、脂质堆积和胶原沉积；PTUPB亦可降低HFD小鼠肝组织基质金属蛋白酶抑制因子Timp1及Timp2的基因表达；...

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

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.