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

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34118488", "kind": "science-record", "revision": 8, "content_hash": "sha256:c3afe2bf9f57a87cbf98f12560798f2f63c359ad02c80fb084570b29d8322a0c", "created_at": "2026-11-01T15:41:38Z", "updated_at": "2026-11-01T22:03:56Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Fatty Acids Activate the Transcriptional Coactivator YAP1 to Promote Liver Fibrosis via p38 Mitogen-Activated Protein Kinase.", "doi": "10.1016/j.jcmgh.2021.06.003", "pmid": "34118488", "authors": ["Shadi Salloum", "Andre J Jeyarajan", "Annie J Kruger", "Jacinta A Holmes", "Tuo Shao", "Mozhdeh Sojoodi", "Myung-Ho Kim", "Zhu Zhuo", "Stuti G Shroff", "Andrew Kassa", "Kathleen E Corey", "Sanjoy K Khan", "Wenyu Lin", "Nadia Alatrakchi", "Esperance A K Schaefer", "Raymond T Chung"], "journal": "Cellular and molecular gastroenterology and hepatology", "year": 2021, "abstract": "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.\nMETHODS: 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.\nRESULTS: 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.\nCONCLUSIONS: 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.", "claims": [{"id": "claim-method", "statement": "Human data were compared using Fisher’s exact test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34118488", "locator": "sections[20] \"Statistical Analysis\" paragraph 3", "quote": "Human data were compared using Fisher’s exact test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "We utilized GEO data (accession: GSE162694) (G. Agyapongm, MD et al, 2020, unpublished data), which includes RNAseq data for 143 NAFLD patients with various stages of fibrosis.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34118488", "locator": "sections[14] \"Human Samples and Histopathological Analysis\" paragraph 2", "quote": "We utilized GEO data (accession: GSE162694) (G. Agyapongm, MD et al, 2020, unpublished data), which includes RNAseq data for 143 NAFLD patients with various stages of fibrosis."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:34118488"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE162694"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE162694"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34118488", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1016/j.jcmgh.2021.06.003", "sha256": "sha256:60d9fe09cfe3bd9d2d916d7def80da9d4c036f1b6c2871f55b4c33720df32cba", "bytes": 48821, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1016/j.jcmgh.2021.06.003", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8463869", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE162694", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162694", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE162694", "version": null, "note": "We utilized GEO data (accession: GSE162694) (G. Agyapongm, MD et al, 2020, unpublished data), which includes RNAseq data for 143 NAFLD patients with various stages of fibrosis.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "We utilized GEO data (accession: GSE162694) (G. 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"version": null, "note": "Demographic and Patient Characteristics", "structure": {"pmcid": "PMC8463869", "section_index": 7, "section_title": "YAP Is Activated in the Livers of Humans With NAFLD-Related Fibrosis", "row_count": 6, "column_count": 6}, "table": {"label": "Table 1", "caption": "Demographic and Patient Characteristics", "rows": [["", "All Patients (N = 182)", "Normal Histology (n = 41)", "Steatosis (n = 45)", "F1–2 (n = 81)", "F3–4 (n = 33)"], ["Male", "35", "22.5", "33.3", "36.2", "53.7"], ["BMI, kg/m2", "41.4 ± 10.3", "41.4 ± 4.4", "46.6 ± 10.2", "38.8 ± 11", "36.1 ± 11.7"], ["Diabetes", "33.5", "15", "24.4", "37.7", "85.7"], ["ALT, U/L", "36.6 ±19.2", "22.9 ± 12.1", "29.9 ± 9.6", "41.8 ± 21", "53.3 ± 18"], ["AST, U/L", "30 ± 15.8", "19.1 ± 5", "22.7 ± 4.8", "33.1 ± 16", "48.8 ± 19.5"]], "row_count": 6, "column_count": 6, "numeric_cells": 30, "header_rows": 1, "locator": "section[7]/table-wrap[1]#tbl1"}}], "gaps": ["asset:data:geo:GSE162694 not downloaded", 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METHODS: We analyzed RNA sequencing data from a GEO DataSet (accession: GSE16269", "al, 2020, unpublished data), which includes RNAseq data for 143 NAFLD patients with various sta"], "order_basis": "paper_text_order:764", "id": "assay:1"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["f 143 patients with NAFLD. We also performed immunohistochemical, immunofluorescence, immunoblot, and quantit", "AFLD. We also performed immunohistochemical, immunofluorescence, immunoblot, and quantitative reverse-transc"], "order_basis": "paper_text_order:882", "id": "assay:2"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["med immunohistochemical, immunofluorescence, immunoblot, and quantitative reverse-transcription poly", "-transcription polymerase chain reaction and immunoblot studies at the specified time points, and da", "e, San Diego, CA). Densitometric analyses of immunoblot images were performed using Image Studio Lit"], "order_basis": "paper_text_order:923", "id": "assay:3"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["liver specimens from NAFLD subjects, from a murine dietary NAFLD model, and in FFA-treated hepa", "iet. Hepatocyte-specific YAP deletion in the murine NAFLD model attenuated diet-induced fibrosis", "LD patients and was associated with fibrosis in mice fed a NAFLD-inducing diet. Hepatocyte-specif", "20). Animal Studies Alb-Cre and Yapflox/flox mice were purchased from the Jackson Laboratory (Bar H"], "order_basis": "paper_text_order:1067", "id": "assay:4"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["lected as previously described.28 Cells were cultured in Dulbecco's modified Eagle's medium supplemen", "mittee of MGH. Cell Culture We used Huh7 and HepG2 human hepatoma cells, Human Embryonic Kidney"], "order_basis": "paper_text_order:3885", "id": "assay:5"}, {"role": "analysis", "definition_id": "image_quantification", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["segment_objects", "quantify_intensity"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["Densitometr"], "order_basis": "consumes_earlier_output", "id": "assay:6"}]}