Elsiad Engy A, Abd El Aal Hayat A, Salem Hesham A, El-Yamany Mohammed F, Rabie Mostafa A
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Department of Clinical, Bio-in Molecules, Egyptian Drug Authority (EDA), Cairo 11553, Egypt.
Toxics. 2025 Jul 16;13(7):594. doi: 10.3390/toxics13070594.
HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis.
3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，即他汀类药物，被广泛用于治疗高脂血症、冠状动脉疾病和其他动脉粥样硬化性疾病。然而，他汀类药物治疗的常见副作用之一是肝转氨酶轻度升高，在不到3%的患者中可见。特别是阿托伐他汀和辛伐他汀，最常与他汀类药物引起的肝损伤相关，导致治疗中断。最近的研究强调了胰高血糖素样肽-1受体（GLP-1R）激活在预防肝损伤方面的抗氧化和抗炎特性。尽管如此，GLP-1R激动剂利拉鲁肽（LIRA）对阿托伐他汀（ATO）诱导的肝功能障碍的潜在保护作用尚未完全阐明。在此背景下，本研究旨在探讨LIRA在减轻大鼠ATO诱导的肝损伤中的保护作用，为管理他汀类药物相关肝毒性提供新的见解。事实上，LIRA治疗改善了肝功能酶并减轻了组织病理学改变。LIRA治疗通过增加Nrf2含量和超氧化物歧化酶（SOD）活性来增强抗氧化防御，同时降低NADPH氧化酶。此外，LIRA通过下调HMGB1/TLR-4/RAGE轴并抑制pY323-MAPK p38和pS635-NFκB p65含量的蛋白表达来抑制炎症，从而导致促炎细胞因子（TNF-α和IL-1β）减少。此外，LIRA上调GLP-1R基因表达，并通过激活pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1信号级联促进自噬流入，同时通过降低caspase-3含量抑制细胞凋亡。总之，LIRA通过激活Nrf-2/SOD级联和抑制HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65轴减轻了ATO诱导的氧化应激和炎症。同时，LIRA通过AMPK/ULK1/Beclin-1轴刺激自噬并抑制细胞凋亡，从而恢复自噬和细胞凋亡之间的平衡。
