Fatty Acids Activate the Transcriptional Coactivator YAP1 to Promote Liver Fibrosis via p38 Mitogen-Activated Protein Kinase

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 12; no. 4; pp. 1297 - 1310
• Main Authors: Salloum, Shadi, Jeyarajan, Andre J, Kruger, Annie J, Holmes, Jacinta A, Shao, Tuo, Sojoodi, Mozhdeh, Kim, Myung-Ho, Zhuo, Zhu, Shroff, Stuti G, Kassa, Andrew, Corey, Kathleen E, Khan, Sanjoy K, Lin, Wenyu, Alatrakchi, Nadia, Schaefer, Esperance A.K, Chung, Raymond T
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; Elsevier
• Subjects: Animals; Biomarkers; Computational Biology - methods; Disease Models, Animal; Disease Progression; Disease Susceptibility; Fatty Acids - metabolism; Female; Fibrosis; Gastroenterology and Hepatology; Gene Expression Profiling; Gene Expression Regulation; Hepatocytes - metabolism; Humans; Immunohistochemistry; Liver Cirrhosis - etiology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Function Tests; Male; Mice; Models, Biological; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Nonalcoholic Fatty Liver Disease; Original Research; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; YAP; YAP-Signaling Proteins - metabolism; FFA; extracellular signal-regulated kinase; JNK; small interfering RNA; high fat diet; nonalcoholic steatohepatitis; α-SMA; shRNA; short hairpin RNA; pHSC; hepatocellular carcinoma; c-Jun N-terminal kinase; IL; HCC; MAPK; p38 MAPK; green fluorescent protein; choline-deficient; simple steatosis; Massachusetts General Hospital; Fibrosis; CDAHFD; primary human hepatocyte; ERK; α-smooth muscle actin; NAFLD; NT; YAP; mRNA; GFP; mitogen-activated protein kinase; PHH; messenger RNA; interleukin; WT; knockout; lipid droplet; RNA sequencing; SS; KO; siRNA; NASH; RNAseq; ECM; MGH; L-amino acid defined; nontargeting; free fatty acid; Nonalcoholic Fatty Liver Disease; LD; wild-type; extracellular matrix; primary human hepatic stellate cell
• DOI: 10.1016/j.jcmgh.2021.06.003
• ISSN: 2352-345X

Background & AimsPatients 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. MethodsWe 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. ResultsYAP-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. ConclusionsThese 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.