scholarly journals Lack of Glycoprotein 130/Signal Transducer and Activator of Transcription 3-Mediated Signaling in Hepatocytes Enhances Chronic Liver Injury and Fibrosis Progression in a Model of Sclerosing Cholangitis

2010 ◽  
Vol 176 (5) ◽  
pp. 2236-2246 ◽  
Author(s):  
Werner Plum ◽  
Darjus F. Tschaharganeh ◽  
Daniela C. Kroy ◽  
Eva Corsten ◽  
Stephanie Erschfeld ◽  
...  
Keyword(s):  
Liver Injury ◽  
Sclerosing Cholangitis ◽  
Chronic Liver ◽  
Signal Transducer ◽  
Chronic Liver Injury ◽  
Fibrosis Progression ◽  
Transcription 3

Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver

Gut ◽  
2018 ◽  
Vol 68 (3) ◽  
pp. 522-532 ◽  
Author(s):  
Aida Habib ◽  
Dina Chokr ◽  
JingHong Wan ◽  
Pushpa Hegde ◽  
Morgane Mabire ◽  
...  
Keyword(s):  
Liver Injury ◽  
Cannabinoid Receptor ◽  
Chronic Liver ◽  
Autophagic Flux ◽  
Monoacylglycerol Lipase ◽  
Chronic Liver Injury ◽  
Fibrosis Progression ◽  
Duct Ligation ◽  
Anti Inflammatory ◽  
The Impact

ObjectiveSustained inflammation originating from macrophages is a driving force of fibrosis progression and resolution. Monoacylglycerol lipase (MAGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. It is a proinflammatory enzyme that metabolises 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury.DesignC57BL/6J mice and mice with global invalidation of MAGL (MAGL-/-), or myeloid-specific deletion of either MAGL (MAGLMye-/-), ATG5 (ATGMye-/-) or CB2 (CB2Mye-/-), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl4) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells.ResultsMAGL-/- or MAGLMye-/- mice exposed to CCl4 or subjected to BDL were more resistant to inflammation and fibrosis than wild-type counterparts. Therapeutic intervention with MJN110, an MAGL inhibitor, reduced hepatic macrophage number and inflammatory gene expression and slowed down fibrosis progression. MAGL inhibitors also accelerated fibrosis regression and increased Ly-6Clow macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGLMye-/- BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGLMye-/- mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2Mye-/- mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5Mye-/- BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited.ConclusionMAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury.

Signal Transducer and Activator of Transcription 3 Protects From Liver Injury and Fibrosis in a Mouse Model of Sclerosing Cholangitis

2010 ◽  
Vol 138 (7) ◽  
pp. 2499-2508 ◽  
Author(s):  
Markus Mair ◽  
Gernot Zollner ◽  
Doris Schneller ◽  
Monica Musteanu ◽  
Peter Fickert ◽  
...  
Keyword(s):  
Liver Injury ◽  
Mouse Model ◽  
Sclerosing Cholangitis ◽  
Signal Transducer ◽  
Transcription 3

Ductular reactions provide a structural biliary network to preserve bile drainage in the CDE-model of hepatocellular chronic liver injury

2017 ◽  
Vol 66 (1) ◽  
pp. S6
Author(s):  
L.-A. Clerbaux ◽  
R. Manco ◽  
N. Van Hul ◽  
R. Español-Suñer ◽  
C. Bouzin ◽  
...  
Keyword(s):  
Liver Injury ◽  
Chronic Liver ◽  
Chronic Liver Injury ◽  
Bile Drainage

Gab1 in livers with persistent hepatocyte apoptosis has an antiapoptotic effect and reduces chronic liver injury, fibrosis and tumorigenesis

2021 ◽  
Author(s):  
Tetsuo Takehara ◽  
Naoki Mizutani ◽  
Hayato Hikita ◽  
Yoshinobu Saito ◽  
Yuta Myojin ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Liver Injury ◽  
Cell Viability ◽  
Liver Regeneration ◽  
Adaptor Protein ◽  
Chronic Liver ◽  
Hepatocyte Apoptosis ◽  
Chronic Liver Injury ◽  
The Impact

Grb2-associated binder 1 (Gab1) is an adaptor protein that is important for intracellular signal transduction by receptor tyrosine kinases that are receptors for various growth factors and plays an important role in rapid liver regeneration after partial hepatectomy and during acute hepatitis. On the other hand, mild liver regeneration is induced in livers of individuals with chronic hepatitis, where hepatocyte apoptosis is persistent; however, the impact of Gab1 on such livers remains unclear. We examined the role of Gab1 in chronic hepatitis. Gab1 knockdown enhanced the decrease in cell viability and apoptosis induced by ABT-737, a Bcl-2/-xL/-w inhibitor, in BNL.CL2 cells, while cell viability and caspase activity were unchanged in the absence of ABT-737. ABT-737 treatment induced Gab1 cleavage to form p35-Gab1. p35-Gab1 was also detected in the livers of mice with hepatocyte-specific Mcl-1 knockout (KO), which causes persistent hepatocyte apoptosis. Gab1 deficiency exacerbated hepatocyte apoptosis in Mcl-1 KO mice with posttranscriptional downregulation of Bcl-XL. In BNL.CL2 cells treated with ABT-737, Gab1 knockdown posttranscriptionally suppressed Bcl-xL expression, and p35-Gab1 overexpression enhanced Bcl-xL expression. Gab1 deficiency in Mcl-1 KO mice activated STAT3 signaling in hepatocytes, increased hepatocyte proliferation, and increased the incidence of liver cancer with the exacerbation of liver fibrosis. In conclusion, Gab1 is cleaved in the presence of apoptotic stimuli and forms p35-Gab1 in hepatocytes. In chronic liver injury, the role of Gab1 in suppressing apoptosis and reducing liver damage, fibrosis, and tumorigenesis is more important than its role in liver regeneration.

scholarly journals CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism

Gut ◽  
2015 ◽  
Vol 65 (7) ◽  
pp. 1175-1185 ◽  
Author(s):  
Annika Wilhelm ◽  
Victoria Aldridge ◽  
Debashis Haldar ◽  
Amy J Naylor ◽  
Christopher J Weston ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Injury ◽  
Hepatic Stellate Cell ◽  
Stellate Cell ◽  
Chronic Liver ◽  
Chronic Liver Injury
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