| First Author | Xu C | Year | 2024 |
| Journal | Toxicol Sci | PubMed ID | 38180883 |
| Mgi Jnum | J:344228 | Mgi Id | MGI:7572667 |
| Doi | 10.1093/toxsci/kfad132 | Citation | Xu C, et al. (2024) Hepatocyte miR-21-5p-deficiency Alleviates APAP-Induced Liver injury by inducing PPARgamma and Autophagy. Toxicol Sci |
| abstractText | 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 in 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 to WT mice, miR-21 HKO mice showed an increased survival, a reduction of necrotic hepatocytes, and an increased expression of light chain 3B (LC3B), which suggested an autophagy activation. The expression of PPARgamma was highly induced in 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 PPARgamma protein expression by targeting its 3'-UTR. When PPARgamma function was blocked by a potent antagonist GW9662 in miR-21-HKO mice, the autophage activation was significantly diminished, suggesting an indispensable role of PPARgamma signaling pathway in miR-21-mediated hepatotoxicity. Taken together, hepatocyte-specific depletion of miRNA-21 alleviated APAP-induced hepatotoxicity by activating PPARgamma and autophagy, demonstrating a crucial new regulatory role of miR-21 in APAP-mediated liver injury. |
