Oxidative and ER stress-dependent ASK1 activation in steatotic hepatocytes and Kupffer cells sensitizes mice fatty liver to ischemia/reperfusion injury

Imarisio, Chiara; Alchera, Elisa; Revanna, Chandrashekar Bangalore; Valente, Guido; Follenzi, Antonia; Trisolini, Elena; Boldorini, Renzo; Carini, Rita

doi:10.1016/j.freeradbiomed.2017.07.020

Cited by 42 publications

(47 citation statements)

References 28 publications

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“…Hepatocyte lipoapoptosis represents one of the most important pathogenic events in NASH, which releases hepatocyte‐derived factors to activate macrophages and quiescent HSCs, leading to the progression of hepatic inflammation and fibrosis in NASH . ASK1, a key facilitator of apoptosis, is highly sensitive to lipotoxicity and contributes substantially to hepatocellular cell death . To elucidate the role of ASK1 in hepatocytes under metabolic stress, we performed DGE analysis of mRNAs from mock‐ or ASK1‐transfected human L02 hepatocytes in response to palmitic acid (PA) challenge.…”

Section: Resultsmentioning

confidence: 99%

“…(9,10) ASK1, a key facilitator of apoptosis, is highly sensitive to lipotoxicity and contributes substantially to hepatocellular cell death. (24,25) To elucidate the role of ASK1 in hepatocytes under metabolic stress, we performed DGE analysis of mRNAs from mock-or ASK1-transfected human L02 hepatocytes in response to palmitic acid (PA) challenge. Notably, KEGG pathway enrichment analysis suggested that the ASK1-potentiated differently expressed genes (DEGs) are mainly involved in inflammation-related pathways, including the interleukin-17 (IL-17) signaling pathway, TNF signaling pathway, and mitogen-activated protein kinase (MAPK) signaling pathway ( Fig.…”

Section: Hyperactivated Ask1 In Hepatocyte Drives Hepatocyte Inflammamentioning

confidence: 99%

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Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Wang

Wen

et al. 2019

Hepatology

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Activation of apoptosis signal‐regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte‐derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor–associated factor 6 (TRAF6) promotes lysine 6 (Lys6)‐linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the in vitro findings, diet‐induced liver inflammation and fibrosis were substantially attenuated in Traf6+/– mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6‐linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N‐terminal dimerization of ASK1, resulting in the boosted activation of ASK1‐c‐Jun N‐terminal kinase 1/2 (JNK1/2)‐mitogen‐activated protein kinase 14(p38) signaling cascade in hepatocytes. Conclusion: These results suggest that Lys6‐linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6‐linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Hyperactivated Ask1 In Hepatocyte Drives Hepatocyte Inflammamentioning

confidence: 99%

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Wang

Wen

et al. 2019

Hepatology

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“…Many other drugs affecting intracellular inflammatory or metabolic pathways are currently being evaluated as potential treatments for NAFLD ( 4 ). Among them, the apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib blocks inflammatory signaling (JNK and p38 MAPK) in KCs ( 160 ), which might explain antifibrotic signals observed in an early clinical trial ( 161 ).…”

Section: Modulating Myeloid-derived Cells In Fatty Liver Diseasementioning

confidence: 99%

Adapted Immune Responses of Myeloid-Derived Cells in Fatty Liver Disease

2018

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Non-alcoholic fatty liver disease (NAFLD) is considered to be one of the most frequent chronic liver diseases worldwide and is associated with an increased risk of developing liver cirrhosis and hepatocellular carcinoma. Hepatic macrophages, mainly comprising monocyte derived macrophages and tissue resident Kupffer cells, are characterized by a high diversity and plasticity and act as key regulators during NAFLD progression, in conjunction with other infiltrating myeloid cells like neutrophils or dendritic cells. The activation and polarization of myeloid immune cells is influenced by dietary components, inflammatory signals like danger-associated molecular patterns (DAMPs) or cytokines as well as gut-derived inflammatory factors such as pathogen-associated molecular patterns (PAMPs). The functionality of myeloid leukocytes in the liver is directly linked to their inflammatory polarization, which is shaped by local and systemic inflammatory mediators such as cytokines, chemokines, PAMPs, and DAMPs. These environmental signals provoke intracellular adaptations in myeloid cells, including inflammasome and transcription factor activation, inflammatory signaling pathways, or switches in cellular metabolism. Dietary changes and obesity also promote a dysbalance in intestinal microbiota, which can facilitate intestinal permeability and bacterial translocation. The aim of this review is to highlight recent findings on the activating pathways of innate immune cells during the progression of NAFLD, dissecting local hepatic and systemic signals, dietary and metabolic factors as well as pathways of the gut-liver axis. Understanding the mechanism by which plasticity of myeloid-derived leukocytes is related to metabolic changes and NAFLD progression may provide options for new therapeutic approaches.

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“…As a member of the MAP3K family, ASK1 dimerization and phosphorylation further activates the MKK4/MKK7‐JNK and MKK3/MKK6‐p38 pathways, which are general mediators of cell death and inflammation in response to various stimuli, e.g., oxidative stress, endoplasmic reticulum (ER) stress, TNFα, and lipopolysaccharide . Previous studies indicated that oxidative and ER stress–induced ASK1 activation in steatotic hepatocytes sensitizes mice fatty liver to IR injury . Notably, ASK1 inhibitors have been applied in IR injury of other tissues and have shown therapeutic effects in rodent models.…”

Section: Discussionmentioning

confidence: 99%

Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia‐Reperfusion Injury in Mice

et al. 2019

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Hepatic ischemia-reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR-induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll-interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by Tollip deficiency both in vivo and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal-regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N-terminal dimerization and the subsequent activation of downstream mitogen-activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip-regulated ASK1-MAPK axis activation. Conclusion: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N-terminal dimerization and the resultant c-Jun N-terminal kinase/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury.

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Oxidative and ER stress-dependent ASK1 activation in steatotic hepatocytes and Kupffer cells sensitizes mice fatty liver to ischemia/reperfusion injury

Cited by 42 publications

References 28 publications

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Adapted Immune Responses of Myeloid-Derived Cells in Fatty Liver Disease

Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia‐Reperfusion Injury in Mice

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