Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, 116044, China.
Department of Biotechnology, Dalian Medical University, Dalian, Liaoning, 116044, China.
Biochem Biophys Res Commun. 2018 Nov 30;506(3):611-618. doi: 10.1016/j.bbrc.2018.10.122. Epub 2018 Oct 24.
Diabetes mellitus (DM) associated liver damage is a major health burden. Hepatocellular-damage in DM characterized with elevated endoplasmic reticulum stress (ER) and may enhanced insulin-resistance. Phosphocreatine (PCr) a rapidly high-energy-reserve molecule of phosphates naturally occurs in liver, brain and skeletal muscle. This study aimed to investigate the protective effect of PCr on the liver-injury-associated with DM and to report the mechanism involved. Wistar rat's diabetes model was induced using streptozotocin (STZ), and the animals were treated with 20 mg/kg, or 50 mg/kg PCr injection. Blood glucose level, and body wt were recorded. Liver tissues homogenate were analyzed for liver damage markers alanine transaminase (ALT), aspartate transaminase (AST). Liver tissues proteins further evaluated for apoptosis, endoplasmic reticulum stress (ER), and insulin resistance biomarkers using western blotting. Our results revealed that PCr reduced blood glucose level, improved body wt, ameliorates liver function enzymes. Furthermore, PCr upregulates anti-apoptotic Bcl2 proteins expression, and down-regulates significantly pro-apoptotic casp3 and Bax proteins expression in vivo and invitro. Moreover, ER stress CHOP, GRP78 and ATF4 biomarkers level were significantly attenuated in PCr treated animals comparing to STZ diabetes associated liver-damage model with significant improving in insulin-resistance Akt and IRS-1. Our results revealed that treating with PCr in diabetes-associated liver injury models decreased blood glucose level and possess protective effect in-vitro and in-vivo, which could be suggested as potential therapeutic strategy for diabetes associated liver injury patients.
糖尿病（DM）相关的肝损伤是一个主要的健康负担。DM 中的肝细胞损伤表现为内质网应激（ER）升高，并可能增强胰岛素抵抗。磷酸肌酸（PCr）是一种天然存在于肝脏、大脑和骨骼肌中的快速高能磷酸盐储备分子。本研究旨在探讨 PCr 对 DM 相关肝损伤的保护作用，并报告相关机制。使用链脲佐菌素（STZ）诱导 Wistar 大鼠糖尿病模型，并用 20mg/kg 或 50mg/kg PCr 注射液对动物进行治疗。记录血糖水平和体重。分析肝组织匀浆中的丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）等肝损伤标志物。进一步用 Western blot 法评估肝组织蛋白中的凋亡、内质网应激（ER）和胰岛素抵抗生物标志物。我们的结果表明，PCr 降低了血糖水平，改善了体重，改善了肝功能酶。此外，PCr 在体内和体外均上调了抗凋亡 Bcl2 蛋白的表达，并显著下调了促凋亡 casp3 和 Bax 蛋白的表达。此外，与 STZ 糖尿病相关的肝损伤模型相比，PCr 处理的动物 ER 应激 CHOP、GRP78 和 ATF4 生物标志物水平显著降低，胰岛素抵抗 Akt 和 IRS-1 显著改善。我们的结果表明，在糖尿病相关的肝损伤模型中，用 PCr 治疗可降低血糖水平，并具有体内和体外的保护作用，这可能为糖尿病相关肝损伤患者提供潜在的治疗策略。
