Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation

Shan, Shulin; Shen, Zhenyu; Zhang, Cuiqin; Kou, Ruirui; Xie, Keqin; Song, Fuyong

doi:10.1016/j.bcp.2019.113643

Cited by 72 publications

(33 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given the central role of mitochondria in the pathophysiology of APAP-induced cell death, the removal of damaged mitochondria and mitochondrial protein adducts by mitophagy is feasible to be a defensive mechanism in the liver for promoting the recovery from APAP-induced injury. It has been demonstrated that pharmacological induction of autophagy by rapamycin almost completely eliminates APAP-induced liver injury in mice, whereas inhibition of autophagy by 3-methyladenine or chloroquine can further exacerbate APAP-induced hepatotoxicity [156,157]. Baulies et al reported that mice with lysosome dysfunction exhibit a higher mortality after APAP overdose due to impaired fusion of mitochondria-containing autophagosomes with lysosomes [158].…”

Section: Mitophagy In Drug-induced Liver Injurymentioning

confidence: 99%

“…This is likely because PINK1-mediated mitophagy still occurs in the absence of Parkin, which may compensate for the lack of Parkin. However, acute knockdown of Parkin accelerated APAP-induced liver injury in mice, inferring that under the acute knockdown of the Parkin time window the mice do not have sufficient time to adapt to the acute loss of Parkin [157]. Indeed, our recent work revealed that very low levels of mitophagy were detected in the PINK1/Parkin double-knockout mouse livers with or without APAP treatment, and the PINK1/Parkin double-knockout mice have the most severe liver injury compared with wild-type or either of the single knockout mice [159].…”

Section: Mitophagy In Drug-induced Liver Injurymentioning

confidence: 99%

“…ALD [114,116,119,122] NAFLD [134,140] DILI [155,157,159] HBV/HCV [192] Cancer [216] The expression level of fluorescent proteins varies in different cells/tissues Not robust and easy to be dependent on individuals who are performing the quantification. Also, the half-life of the red puncta in the lysosomes may be dependent on cellular context and conditions, e.g., the activities of the lysosomal proteases NAFLD [86] DILI [159] Cancer [216] 6.…”

Section: Analysis Of Mitophagy In the Livermentioning

confidence: 99%

See 2 more Smart Citations

Role and Mechanisms of Mitophagy in Liver Diseases

McKeen

Zhang

et al. 2020

Cells

178

122

View full text Add to dashboard Cite

The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.

show abstract

Section: Mitophagy In Drug-induced Liver Injurymentioning

confidence: 99%

Section: Mitophagy In Drug-induced Liver Injurymentioning

confidence: 99%

Section: Analysis Of Mitophagy In the Livermentioning

confidence: 99%

See 1 more Smart Citation

Role and Mechanisms of Mitophagy in Liver Diseases

McKeen

Zhang

et al. 2020

Cells

178

122

View full text Add to dashboard Cite

show abstract

“…20 In a recent study, we found that autophagyactivating agent rapamycin can significantly inhibit the activation of NLPR3 inflammasome and protect against APAP-induced liver damage, which further supports the critical role of NLPR3 inflammasome activation in APAP liver toxicity. 21 Despite the critical role of necroptosis and NLRP3 inflammasome in APAP-induced liver injury, the time-course of them in the pathogenesis of APAP liver injury is still largely unknown. Especially, the causal relationship between necroptosis and inflammation signaling pathways in APAP-induced liver injury remains elusive.…”

Section: Introductionmentioning

confidence: 99%

The cross-talk of NLRP3 inflammasome activation and necroptotic hepatocyte death in acetaminophen-induced mice acute liver injury

Shan

Kang

et al. 2020

Hum Exp Toxicol

View full text Add to dashboard Cite

Overdose acetaminophen (APAP) can result in severe liver injury, which is responsible for nearly half of drug-induced liver injury in western countries. Previous studies have found that there existed massive hepatocellular necrosis and severe inflammatory response in APAP-induced liver injury. However, the mechanistic linkage between necroptosis and NLRP3 inflammasome pathway in APAP-induced hepatotoxicity remains poorly understood. In order to investigate the relationship between inflammation and hepatocytes death in APAP hepatotoxicity, a time-course model for APAP hepatotoxicity in C57/BL6 mice was established by intraperitoneal (i.p) injection of 300 mg/kg APAP in this study. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in necroptosis and NF-κB-NLRP3 inflammasome signaling pathway were determined by immunoblot and immunofluorescence analysis. The results demonstrated that APAP overdose resulted in a severe liver injury. Furthermore, the expression of critical molecules in NLRP3 inflammasome and necroptosis pathways peaked at 12–24 h, and then was decreased gradually, which is consistent with the pattern of pathological injury induced by APAP. Our further investigation found that the level of IL-1β in mouse liver was closely correlated with the level of phosphorylated MLKL following exposure to APAP. Furthermore, inhibition of necroptosis with necrostatin-1 significantly suppressed the activation of NLRP3 inflammasome signaling. Taken together, our results highlighted that the cross-talk between necroptosis and NLRP3 inflammasome played a critical role for promoting APAP-induced liver injury. Inhibition of the interaction of inflammation and necroptosis by pharmaceutical methods may represent a promising therapeutic strategy for APAP-induced liver injury.

show abstract

“…Multiple pathways are related to the effects of TSG on APAP‐induced liver damage. First, basal autophagy contributes to efficient quality control of organelles and cytosolic proteins in hepatocytes (Shan et al, 2019). Autophagic dysfunction is associated with a variety of liver diseases such as alcoholic liver disease, nonalcoholic fatty liver, DILI, and liver tumors (Ueno & Komatsu, 2017).…”

Section: Introductionmentioning

confidence: 99%

Tetrahydroxy stilbene glycoside attenuates acetaminophen‐induced hepatotoxicity by UHPLC‐Q‐TOF/MS‐based metabolomics and multivariate data analysis

Gao

Li³

et al. 2020

Journal Cellular Physiology

View full text Add to dashboard Cite

Tetrahydroxy stilbene glycoside (TSG) is a main active compound in Polygonum multiflorum. Acetaminophen (APAP) is a well‐known analgesic and antipyretic drug. It is considered to be safe within a therapeutic range, in case of acute intoxication hepatotoxicity occurs. This present study aims to observe TSG‐provided alleviation on APAP‐induced hepatoxicity in C57BL/6 mice. APAP performs extensive necrosis and dissolves nucleus suggesting liver damage from hepatic histopathology. Serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase analysis and liver histological evaluation showed that TSG reduced the hepatotoxicity induced by a toxic dose of APAP. Moreover, TSG alone had no hepatotoxicity. TSG eliminated hepatic glutathione depletion and cysteine adducts formation. It also reduced the expression of interleukin‐10 and lowered the production of reactive oxygen species in liver tissues. Luminex was used to detect cytokine production in different groups. Herein, we used an untargeted metabolomics approach by performing ultrahigh‐performance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry on treated mice to identify metabolic disruptions under APAP and TSG. Major alterations were observed for purine metabolism, amino acid metabolism, and fatty acid metabolism. These data provide metabolic evidence and biomarkers in the liver that the ABC transporters, Glycine serine and threonine metabolism, and Choline metabolism in cancer changed the most. These targets of metabolites have the potential to improve our understanding of homeostatic. Meanwhile, these metabolites revealed that TSG can alleviate inflammation caused by APAP and promote the activity of intrinsic antioxidants. In summary, TSG can regulate lipid metabolism, promote the production of antioxidant enzymes, and decrease the inflammatory response.

show abstract

Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation

Cited by 72 publications

References 39 publications

Role and Mechanisms of Mitophagy in Liver Diseases

Role and Mechanisms of Mitophagy in Liver Diseases

The cross-talk of NLRP3 inflammasome activation and necroptotic hepatocyte death in acetaminophen-induced mice acute liver injury

Tetrahydroxy stilbene glycoside attenuates acetaminophen‐induced hepatotoxicity by UHPLC‐Q‐TOF/MS‐based metabolomics and multivariate data analysis

Contact Info

Product

Resources

About