Department of Pathophysiology, Chengde Medical University, Chengde, Hebei 067000, P.R. China.
Department of Medicine, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China.
Mol Med Rep. 2021 Apr;23(4). doi: 10.3892/mmr.2021.11923. Epub 2021 Feb 19.
Hepatic steatosis, an indicator of atherosclerosis (AS), is always accompanied by inflammatory responses and disturbances in lipid metabolism. The present study investigated the protective effect of urantide, a urotensin II (UII) receptor antagonist, on the liver of rats with AS with hepatic steatosis by regulating the MAPK pathway. AS was induced in rats via an intraperitoneal injection of vitamin D3 and the administration of a high‑fat diet. Urantide treatment was then administered to the rats. Pathology, liver index, lipid levels and liver function were measured to determine liver injury. The expression levels of UII and G protein‑coupled receptor 14 (GPR14) were determined using immunohistochemistry, reverse transcription‑quantitative PCR and western blotting. The expression levels of MAPK‑related proteins in hepatocytes from each group were quantified using western blotting and immunofluorescence staining. Rats with AS had typical pathological changes associated with AS and hepatic steatosis, which were significantly improved by urantide treatment. Blood lipid levels, body weight, liver index and liver function were recovered in rats with AS after urantide treatment. Urantide downregulated the expression levels of UII and GPR14 in the livers of rats with AS; concurrently, the phosphorylation of Erk1/2 and JNK was significantly decreased. Moreover, no significant changes were observed in the phosphorylation of p38 MAPK in AS rat livers. In conclusion, urantide inhibits the activation of Erk1/2 and JNK by blocking the binding of UII and GPR14, thereby alleviating hepatic steatosis in rats with AS, ultimately restoring lipid metabolism in the liver and alleviating AS lesions.
肝脂肪变性是动脉粥样硬化（AS）的一个指标，总是伴随着炎症反应和脂质代谢紊乱。本研究通过调节 MAPK 通路，探讨了 UII 受体拮抗剂尿鸟苷肽（Urantide）对伴有肝脂肪变性的 AS 大鼠肝脏的保护作用。通过腹腔注射维生素 D3 和给予高脂肪饮食诱导大鼠 AS，然后给予 Urantide 治疗。通过病理学、肝指数、血脂水平和肝功能测定来衡量肝损伤。通过免疫组织化学、逆转录定量 PCR 和 Western blot 测定 UII 和 G 蛋白偶联受体 14（GPR14）的表达水平。使用 Western blot 和免疫荧光染色定量测定各组肝细胞中 MAPK 相关蛋白的表达水平。AS 大鼠具有典型的 AS 和肝脂肪变性相关的病理变化，经 Urantide 治疗后明显改善。AS 大鼠经 Urantide 治疗后血脂水平、体重、肝指数和肝功能恢复正常。Urantide 下调 AS 大鼠肝脏中 UII 和 GPR14 的表达水平；同时，Erk1/2 和 JNK 的磷酸化明显降低。此外，在 AS 大鼠肝组织中未观察到 p38 MAPK 磷酸化的显著变化。总之，Urantide 通过阻断 UII 和 GPR14 的结合抑制 Erk1/2 和 JNK 的激活，从而缓解 AS 大鼠的肝脂肪变性，最终恢复肝脏的脂质代谢，减轻 AS 病变。
