Liver‐specific deficiency of unc‐51 like kinase 1 and 2 protects mice from acetaminophen‐induced liver injury

Sun, Yu; Li, Terytty Yang; Song, Lintao; Zhang, Cixiong; Li, Jingyi; Lin, Zhi-Zhong; Lin, Sheng-Cai; Lin, Shu-Yong

doi:10.1002/hep.29759

Cited by 33 publications

(23 citation statements)

References 47 publications

(147 reference statements)

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“…More recently, Sun et al found that ULK1/ULK2 double KO mice are also resistant to APAP‐induced liver injury. Surprisingly, ULK1/ULK2 double KO mice have intact hepatic autophagy and therefore no p62‐mediated Nrf2 activation was found in ULK1/ULK2 double KO mice . Instead, ULK1 is required for the maximum activation hepatic JNK in response to APAP treatment.…”

Section: Autophagy Regulates Gsh Biosynthesis and Jnk Activationmentioning

confidence: 98%

“…Mechanistically, APAP inhibits mTORC1 resulting in the release of activated ULK1, which then directly phosphorylates and increases the kinase activity of mitogen‐activated protein kinase kinase 4 and 7 (MKK4/7), the upstream kinases and activator of JNK. Liver‐specific ULK1/ULK2 double KO mice have impaird APAP‐induced JNK activation and are thus resistant to APAP‐induced liver injury . Taken together, it seems that chronic inhibition of autophagy may lead to compensatory non‐canonical activation of Nrf2 and protects against APAP‐induced liver injury.…”

Section: Autophagy Regulates Gsh Biosynthesis and Jnk Activationmentioning

confidence: 98%

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Role and mechanisms of autophagy in acetaminophen‐induced liver injury

Chao

Wang

Jaeschke

et al. 2018

Liver International

117

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Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury.

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Section: Autophagy Regulates Gsh Biosynthesis and Jnk Activationmentioning

confidence: 98%

Section: Autophagy Regulates Gsh Biosynthesis and Jnk Activationmentioning

confidence: 98%

Role and mechanisms of autophagy in acetaminophen‐induced liver injury

Chao

Wang

Jaeschke

et al. 2018

Liver International

117

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“…70 Moreover, unexpectedly, recent data also demonstrate that by promoting activation of c-Jun N-terminal kinase signalling the kinase activities of ULK1/2 are essential in APAP-induced liver injury, independently of their activity in autophagy. 71 Based on the data from these studies, it cannot be excluded that autophagy-dependent and independent ULK1 pathways result in opposing regulation of APAP-induced liver injury.…”

Section: Modulation Of Autophagy For Therapeutic Purposes: a Promisinmentioning

confidence: 99%

Autophagy in liver diseases: Time for translation?

Allaire

Rautou

Codogno

et al. 2019

Journal of Hepatology

298

222

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Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.

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“…65 More recently, unc-51 like autophagy activating kinase (ULK1/2) was identified as another upstream kinase that contributes to JNK activation through phosphorylation of MKK4/7. 66 Activation of JNK occurs early after APAP overdose, with a dose of 300 mg/kg resulting in JNK activation within 1 hour in the cytosol. 62 In addition, glycogen synthase kinase-3β (GSK-3β), a major regulator of glycogen synthase, has also been implicated in JNK activation after APAP.…”

Section: Amplification Of Mitochondrial Dysfunction and Downstream Simentioning

confidence: 99%

Acetaminophen Hepatotoxicity

2019

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Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

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Liver‐specific deficiency of unc‐51 like kinase 1 and 2 protects mice from acetaminophen‐induced liver injury

Abstract: Together, these findings reveal an important role of Ulk1/2 for APAP-induced JNK activation and liver injury, and understanding of this regulatory mechanism may offer us new strategies for prevention and treatment of human APAP hepatotoxicity. (Hepatology 2018;67:2397-2413).

Cited by 33 publications

References 47 publications

Role and mechanisms of autophagy in acetaminophen‐induced liver injury

Role and mechanisms of autophagy in acetaminophen‐induced liver injury

Autophagy in liver diseases: Time for translation?

Acetaminophen Hepatotoxicity

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