| Title | Narirutin activates TFEB (transcription factor EB) to protect against Acetaminophen-induced liver injury by targeting PPP3/calcineurin |
| Authors | Fang, Zhiyuan Xu, Yanyong Liu, Guowen Shao, Qi Niu, Xiaodi Tai, Wenjun Shen, Taiyu Fan, Minghe Chen, Meng Lei, Lin Gao, Wenwen Song, Yuxiang Wang, Zhe Du, Xiliang Li, Xinwei |
| Affiliation | Jilin Univ, Coll Vet Med, State Key Lab Zoonot Dis, Key Lab Zoonosis Res,Minist Educ, 5333 Xian Road, Changchun 130062, Jilin, Peoples R China Fudan Univ, Sch Basic Med Sci, Dept Pathol, Key Lab Metab & Mol Med,Minist Educ, Shanghai, Peoples R China Fudan Univ, Frontier Innovat Ctr, Sch Basic Med Sci, Shanghai, Peoples R China Jilin Univ, Coll Food Sci & Engn, Shanghai, Peoples R China Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biochem & Mol Biol ,Beijing Key Lab Prot Post, Shanghai, Peoples R China |
| Keywords | INDUCED HEPATOTOXICITY RAG GTPASES AUTOPHAGY PROTECTS MECHANISM MICE IDENTIFICATION CALCINEURIN GLUTATHIONE RAGULATOR LYSOSOME |
| Issue Date | Feb-2023 |
| Publisher | AUTOPHAGY |
| Abstract | Acetaminophen (APAP) overdose is the predominant cause of drug-induced liver injury worldwide. The macroautophagy/autophagy-lysosomal pathway (ALP) is involved in the APAP hepatotoxicity. TFEB (transcription factor EB) promotes the expression of genes related to autophagy and lysosomal biogenesis, thus, pharmacological activation of TFEB-mediated ALP may be an effective therapeutic approach for treating APAP-induced liver injury. We aimed to reveal the effects of narirutin (NR), the main bioactive constituents isolated from citrus peels, on APAP hepatotoxicity and to explore its underlying mechanism. Administration of NR enhanced activities of antioxidant enzymes, improved mitochondrial dysfunction and alleviated liver injury in APAP-treated mice, whereas NR did not affect APAP metabolism and MAPK/JNK activation. NR enhanced TFEB transcriptional activity and activated ALP in an MTOR complex 1 (MTORC1)-independent but PPP3/calcineurin-dependent manner. Moreover, knockout of Tfeb or knockdown of PPP3CB/CNA2 (protein phosphatase 3, catalytic subunit, beta isoform) in the liver abolished the beneficial effects of NR on APAP overdose. Mechanistically, NR bound to PPP3CB via PRO31, LYS61 and PRO347 residues and enhanced PPP3/calcineurin activity, thereby eliciting dephosphorylation of TFEB and promoting ALP, which alleviated APAP-induced oxidative stress and liver injury. Together, NR protects against APAP-induced liver injury by activating a PPP3/calcineurin-TFEB-ALP axis, indicating NR may be a potential agent for treating APAP overdose. |
| URI | http://hdl.handle.net/20.500.11897/672167 |
| ISSN | 1554-8627 |
| DOI | 10.1080/15548627.2023.2179781 |
| Indexed | SCI(E) |
| Appears in Collections: | 医学部待认领 |
