Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China.
Toxicol Sci. 2024 Feb 28;198(1):50-60. doi: 10.1093/toxsci/kfad132.
Acetaminophen (APAP)-induced liver injury is one of the most frequent causes of acute liver failure worldwide. Significant increases in the levels of miRNA-21 in both liver tissues and plasma have been observed in APAP-overdosed animals and humans. However, the mechanistic effect of miRNA-21 on acute liver injury remains unknown. In this study, we generated a new hepatocyte-specific miRNA-21 knockout (miR-21-HKO) mouse line. miR-21-HKO and the background-matched sibling wild-type (WT) mice were treated with a toxic dose of APAP. Compared with WT mice, miR-21 HKO mice showed an increased survival, a reduction of necrotic hepatocytes, and an increased expression of light chain 3 beta, which suggested an autophagy activation. The expression of PPARγ was highly induced in the livers of miR-21-HKO mice after a 2-h APAP treatment, which preceded the activation of LC3B at the 12 h APAP treatment. miR-21 negatively regulated PPARγ protein expression by targeting its 3'-UTR. When PPARγ function was blocked by a potent antagonist GW9662 in miR-21-HKO mice, the autophage activation was significantly diminished, suggesting an indispensable role of PPARγ signaling pathway in miR-21-mediated hepatotoxicity. Taken together, hepatocyte-specific depletion of miRNA-21 alleviated APAP-induced hepatotoxicity by activating PPARγ and autophagy, demonstrating a crucial new regulatory role of miR-21 in APAP-mediated liver injury.
对乙酰氨基酚（APAP）诱导的肝损伤是世界范围内急性肝衰竭最常见的原因之一。在 APAP 过量的动物和人类的肝组织和血浆中，miRNA-21 的水平显著增加。然而，miRNA-21 对急性肝损伤的机制作用尚不清楚。在这项研究中，我们生成了一种新的肝细胞特异性 miRNA-21 敲除（miR-21-HKO）小鼠系。miR-21-HKO 和背景匹配的同窝野生型（WT）小鼠用有毒剂量的 APAP 处理。与 WT 小鼠相比，miR-21 HKO 小鼠的存活率提高，坏死肝细胞减少，LC3B 的表达增加，表明自噬激活。在 miR-21-HKO 小鼠的肝脏中，PPARγ 在 2 小时 APAP 处理后高度诱导，LC3B 在 12 小时 APAP 处理时激活之前。miR-21 通过靶向其 3'UTR 负调控 PPARγ 蛋白表达。当 miR-21-HKO 小鼠中的 PPARγ 功能被有效的拮抗剂 GW9662 阻断时，自噬激活明显减少，表明 PPARγ 信号通路在 miR-21 介导的肝毒性中具有不可或缺的作用。总之，肝细胞特异性缺失 miRNA-21 通过激活 PPARγ 和自噬减轻 APAP 诱导的肝毒性，表明 miR-21 在 APAP 介导的肝损伤中具有重要的新调节作用。
