Fatty Acids Activate the Transcriptional Coactivator YAP1 to Promote Liver Fibrosis via p38 Mitogen-Activated Protein Kinase
| Autor: | Nadia Alatrakchi, Tuo Shao, Myung-Ho Kim, Wenyu Lin, Shadi Salloum, Raymond T. Chung, Annie J. Kruger, Andre J Jeyarajan, Kathleen E. Corey, Stuti Shroff, Andrew Kassa, Zhu Zhuo, Sanjoy K. Khan, Mozhdeh Sojoodi, Jacinta A Holmes, Esperance A. Schaefer |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Liver Cirrhosis Male RC799-869 p38 Mitogen-Activated Protein Kinases PHH primary human hepatocyte Mice 0302 clinical medicine ERK extracellular signal-regulated kinase Liver Function Tests Fibrosis Non-alcoholic Fatty Liver Disease Gene expression Nonalcoholic fatty liver disease Medicine L-amino acid defined high fat diet Original Research GFP green fluorescent protein YAP1 Fatty Acids Gastroenterology Diseases of the digestive system. Gastroenterology Immunohistochemistry mRNA messenger RNA ECM extracellular matrix NT nontargeting medicine.anatomical_structure Hippo signaling Hepatocyte JNK c-Jun N-terminal kinase shRNA short hairpin RNA Disease Progression 030211 gastroenterology & hepatology RNAseq RNA sequencing Female CDAHFD choline-deficient Disease Susceptibility YAP NASH nonalcoholic steatohepatitis LD lipid droplet Nonalcoholic Fatty Liver Disease p38 MAPK Models Biological digestive system α-SMA α-smooth muscle actin 03 medical and health sciences FFA free fatty acid Gene silencing Animals Humans KO knockout Hepatology MGH Massachusetts General Hospital business.industry Gene Expression Profiling pHSC primary human hepatic stellate cell Computational Biology YAP-Signaling Proteins medicine.disease WT wild-type SS simple steatosis digestive system diseases IL interleukin Disease Models Animal 030104 developmental biology Gene Expression Regulation siRNA small interfering RNA Hepatic stellate cell Cancer research Hepatocytes NAFLD nonalcoholic fatty liver disease business HCC hepatocellular carcinoma MAPK mitogen-activated protein kinase Biomarkers |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 4, Pp 1297-1310 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | Background & Aims Patients with simple steatosis (SS) and nonalcoholic steatohepatitis can develop progressive liver fibrosis, which is associated with liver-related mortality. The mechanisms contributing to liver fibrosis development in SS, however, are poorly understood. SS is characterized by hepatocellular free fatty acid (FFA) accumulation without lobular inflammation seen in nonalcoholic steatohepatitis. Because the Hippo signaling transcriptional coactivator YAP1 (YAP) has previously been linked with nonalcoholic fatty liver disease (NAFLD)–related fibrosis, we sought to explore how hepatocyte FFAs activate a YAP-mediated profibrogenic program. Methods We analyzed RNA sequencing data from a GEO DataSet (accession: GSE162694) consisting of 143 patients with NAFLD. We also performed immunohistochemical, immunofluorescence, immunoblot, and quantitative reverse-transcription polymerase chain reaction analyses (qRT-PCR) in liver specimens from NAFLD subjects, from a murine dietary NAFLD model, and in FFA-treated hepatic spheroids and hepatocytes. Results YAP-target gene expression correlated with increasing fibrosis stage in NAFLD patients and was associated with fibrosis in mice fed a NAFLD-inducing diet. Hepatocyte-specific YAP deletion in the murine NAFLD model attenuated diet-induced fibrosis, suggesting a causative role of YAP in NAFLD-related fibrosis. Likewise, in hepatic spheroids composed of Huh7 hepatoma cells and primary human hepatic stellate cells, Huh7 YAP silencing reduced FFA-induced fibrogenic gene expression. Notably, inhibition of p38 mitogen-activated protein kinase could block YAP activation in FFA-treated Huh7 cells. Conclusions These studies provide further evidence for the pathological role of YAP in NAFLD-associated fibrosis and that YAP activation in NAFLD may be driven by FFA-induced p38 MAPK activation. Graphical abstract |
| Databáze: | OpenAIRE |
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