Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis

Cubero, Francisco Javier; Peng, Jin; Liao, Lijun; Su, Huan; Zhao, Gang; Zoubek, Miguel Eugenio; Macías-Rodríguez, Ricardo Ulises; Ruiz-Margáin, Astrid; Reißing, Johanna; Zimmermann, Henning W.; Gaßler, Nikolaus; Luedde, Tom; Liedtke, Christian; Hatting, Maximilian

doi:10.1016/j.jhep.2018.08.015

Cited by 20 publications

(36 citation statements)

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“…Apoptosis and necroptosis are two relevant forms of cell death in the pathogenesis of human and murine liver disease. ( 21,22 ) To discriminate between these two types of cell death, we performed immunohistochemistry (IHC) analyses, which revealed significantly higher levels of the apoptosis marker cleaved caspase 3 (CC3) in NEMO ∆hepa /JNK Δhepa livers, especially in cholangiocytes but also in immune infiltrates of these livers (Fig. 2B).…”

Section: Resultsmentioning

confidence: 99%

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

et al. 2020

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Targeted inhibition of the c-Jun N-terminal kinases ( JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)-related tumorigenesis. However, the cell-type-specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO) hepatocyte-specific knockout (Δhepa) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMO Δhepa /JNK1 Δhepa mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMO Δhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMO Δhepa (NEMO Δhepa /JNK Δhepa ) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMO Δhepa /JNK1 Δhepa mice recapitulated the phenotype of NEMO Δhepa /JNK Δhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMO Δhepa mice. We found that NEMO Δhepa /JNK Δhepa livers exhibited overexpression of the interleukin-6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)-rapidly accelerated fibrosarcoma (Raf )-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B-2 (ErbB2) and EGFR signaling, to NEMO Δhepa /JNK Δhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR-Raf-MEK-ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis. (Hepatology Communications 2020;4:834-851). Bile duct hyperplasia and aberrant cholangiocyte growth can result in hepatic cystogenesis, differentially diagnosed on the basis of cholangioma, cholangiofibrosis, intrahepatic cholangiocarcinoma (CCA), and oval cell hyperplasia. (1,2) CCA, a malignancy that arises in the setting of chronic inflammation of biliary epithelium cells, has an increasing incidence and is the second most common primary Abbreviations: α-SMA, alpha smooth muscle actin; Δhepa, hepatocy...

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Section: Resultsmentioning

confidence: 99%

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

et al. 2020

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“…Unfortunately, evidence based-treatment for tackling liver injury is so far unavailable in clinical settings. Moreover, efforts to ameliorate the injury of hepatocytes by regulating their complications, such as intracellular oxidative stress, protein aggregates, and dysfunctional organelles, are far from satisfactory [5][6][7][8]. Thus, it is of immediate significance to explore effective pharmacological antidotes and strategies for liver injury treatment.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Chen

Zai

Fan

et al. 2020

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AbstractInterleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Specifically, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases.Graphical AbstractOur works demonstrate a critical role of IL-22 in regulating hepatocellular metabolism to treat liver injury via activating STAT3-lncRNA H19-AMPK-AKT-mTOR axis. These findings describe a novel mechanism underscoring the regulation of metabolic states of hepatocytes by IL-22 during liver injury with potentially broad therapeutic insights.

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“…This has been explained by inhibition of apoptosis in immune cells, leading to stronger infiltration of mononuclear cells into the liver tissue and to immune cell-mediated liver damage. However, a recent landmark publication demonstrated that cell type-specific deletion of caspase 8 in parenchymal cells of the liver protects against obstructive cholestasis induced by ligation of the common bile duct (Cubero et al 2018). The knockout of caspase 8 in cholangiocytes decreased necrotic foci and ductular reaction (Cubero et al 2018).…”

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confidence: 99%

“…However, a recent landmark publication demonstrated that cell type-specific deletion of caspase 8 in parenchymal cells of the liver protects against obstructive cholestasis induced by ligation of the common bile duct (Cubero et al 2018). The knockout of caspase 8 in cholangiocytes decreased necrotic foci and ductular reaction (Cubero et al 2018). Therefore, caspase 8 is a promising therapeutic target in obstructive cholestasis but strategies have to be identified to inhibit caspase 8 in cholangiocytes without influencing immune cells, because inhibition in immune cells may lead to immune-mediated hepatotoxicity (Cubero et al 2018).…”

mentioning

confidence: 99%

“…The knockout of caspase 8 in cholangiocytes decreased necrotic foci and ductular reaction (Cubero et al 2018). Therefore, caspase 8 is a promising therapeutic target in obstructive cholestasis but strategies have to be identified to inhibit caspase 8 in cholangiocytes without influencing immune cells, because inhibition in immune cells may lead to immune-mediated hepatotoxicity (Cubero et al 2018).…”

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Highlight report: caspase 8 as a therapeutic target in chronic liver disease

Bolt

2019

Arch Toxicol

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Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis

Cited by 20 publications

References 28 publications

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

Highlight report: caspase 8 as a therapeutic target in chronic liver disease

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