Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
Int J Mol Sci. 2022 Jul 8;23(14):7587. doi: 10.3390/ijms23147587.
Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.
对乙酰氨基酚（APAP）是一种广泛使用的解热镇痛药，过量服用会导致急性肝衰竭。慢性酒精性脂肪肝（AFLD）似乎会增加 APAP 诱导的肝损伤的风险和严重程度，同时血管紧张素 II（Ang II）水平急剧升高。然而，其潜在机制尚不清楚。窖蛋白 1（CAV1）已被证明对 AFLD 具有保护作用。本研究旨在通过影响 Ang II 或其相关靶点来研究 CAV1 是否可以保护 AFLD 中 APAP 诱导的肝毒性。在体内，根据慢性加 binge 乙醇模型建立 AFLD 模型。测定肝损伤和肝脂质蓄积水平。通过 Western blot 评估血管紧张素转换酶 2（ACE2）、Ang II、CAV1 和其他相关蛋白的水平。在体外，用酒精和油酸混合物和 APAP 处理 L02 细胞。与 APAP 处理的 AFLD 小鼠相比，APAP 处理的 AFLD 小鼠的 CAV1 和 ACE2 表达下调。在小鼠和 L02 细胞中转染 CAV1 过表达可减轻 AFLD 中 APAP 诱导的肝毒性，并下调 Ang II、p-EGFR/EGFR 和 P-ERK/ERK 的表达。免疫荧光实验显示 CAV1、Ang II 和 EGFR 之间存在相互作用。应用氯沙坦（血管紧张素 II 受体拮抗剂）和 PD98059（ERK1/2 抑制剂）可减轻 AFLD 中 APAP 诱导的肝毒性。总之，我们的研究结果证实 CAV1 通过下调 Ang II/EGFR/ERK 轴减轻 AFLD 中 APAP 加重的肝毒性，这可能成为预防或治疗该病的新治疗靶点。
