Role of receptor interacting protein (RIP)1 on apoptosis-inducing factor-mediated necroptosis during acetaminophen-evoked acute liver failure in mice.
Acetaminophen (APAP) overdose induces apoptosis-inducing factor (AIF)-dependent necroptosis, but the mechanism remains obscure. The present study investigated the role of receptor interacting protein (RIP)1, a critical mediator of necroptosis, on AIF-dependent necroptosis during APAP-induced acute liver failure. Mice were intraperitoneally injected with APAP (300 mg/kg). As expected, hepatic RIP1 was activated as early as 1 h after APAP, which is earlier than APAP-induced hepatic RIP3 upregulation. APAP-evoked RIP1 activation is associated with hepatic glutathione (GSH) depletion. Either pretreatment or post-treatment with Nec-1, a selective inhibitor of RIP1, significantly alleviated APAP-induced acute liver failure. Moreover, Nec-1 improved the survival and prevented APAP-induced necroptosis, as determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay. Further analysis showed that Nec-1 significantly inhibited APAP-induced hepatic c-Jun N-terminal kinase (JNK) phosphorylation and mitochondrial Bax translocation. In addition, Nec-1 blocked APAP-induced translocation of AIF from the mitochondria to the nucleus. Of interest, no changes were induced by Nec-1 on hepatic CYP2E1 expression. In addition, Nec-1 had little effect on APAP-induced hepatic GSH depletion at early stage. Taken together, these results suggest that RIP1 is involved in APAP-induced necroptosis. Nec-1 is an effective antidote for APAP-induced acute liver failure.
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Ye-Fa
YF
Zhang
First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
Wei
W
He
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Cheng
C
Zhang
First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
Xiao-Jing
XJ
Liu
Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
Yan
Y
Lu
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Hua
H
Wang
Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Zhi-Hui
ZH
Zhang
First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
Xi
X
Chen
Department of Toxicology, Anhui Medical University, Hefei 230032, China. Electronic address: xudex@126.com.
De-Xiang
DX
Xu
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism
D051033:Apoptosis Inducing Factor; D020690:GTPase-Activating Proteins; D007093:Imidazoles; D007211:Indoles; C490620:Ralbp1 protein, mouse; C507699:necrostatin-1; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D048031:JNK Mitogen-Activated Protein Kinases
Acetaminophen; Apoptosis-inducing factor (AIF); Necroptosis; Necrostatin-1 (Nec-1); Receptor-interacting protein (RIP) kinases