{"corpus_id":221362281,"paper_sha":"69db5c95aae522f9d70ad664231eefcc9ca6fd9a","doi":"10.7150/thno.45988","arxiv_id":null,"pmid":32929325,"pmcid":"7481424","mag_id":3082188154,"dblp_id":null,"acl_id":null,"title":"Lack of FGF21 promotes NASH-HCC transition via hepatocyte-TLR4-IL-17A signaling","year":2020,"publication_date":"2020-08-07","venue":"Theranostics","journal":{"name":"Theranostics","pages":"9923 - 9936","volume":"10"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, N.I.H., Extramural"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":57,"citation_count":67,"influential_citation_count":5,"is_open_access":false,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"3T3 Cells","mj":false,"ui":"D016475"},{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Carcinoma, Hepatocellular","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"},{"q":"pathology","mj":false,"ui":"Q000473"}],"ui":"D006528"},{"d":"Cells, Cultured","mj":false,"ui":"D002478"},{"d":"Female","mj":false,"ui":"D005260"},{"d":"Fibroblast Growth Factors","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D005346"},{"d":"Hepatocytes","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"},{"q":"pathology","mj":false,"ui":"Q000473"}],"ui":"D022781"},{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Interleukin-17","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D020381"},{"d":"Kupffer Cells","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"},{"q":"pathology","mj":false,"ui":"Q000473"}],"ui":"D007728"},{"d":"Liver Neoplasms","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"},{"q":"pathology","mj":false,"ui":"Q000473"}],"ui":"D008113"},{"d":"Male","mj":false,"ui":"D008297"},{"d":"Mice","mj":false,"ui":"D051379"},{"d":"Mice, Inbred C57BL","mj":false,"ui":"D008810"},{"d":"Mice, Knockout","mj":false,"ui":"D018345"},{"d":"Non-alcoholic Fatty Liver Disease","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"},{"q":"pathology","mj":false,"ui":"Q000473"}],"ui":"D065626"},{"d":"Prospective Studies","mj":false,"ui":"D011446"},{"d":"Signal Transduction","mj":false,"qs":[{"q":"physiology","mj":false,"ui":"Q000502"}],"ui":"D015398"},{"d":"Toll-Like Receptor 4","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D051197"}],"chemicals":[{"n":"FGF21 protein, human","ui":"C000706947","reg":"0"},{"n":"IL17A protein, human","ui":"C508717","reg":"0"},{"n":"Interleukin-17","ui":"D020381","reg":"0"},{"n":"TLR4 protein, human","ui":"C495345","reg":"0"},{"n":"Toll-Like Receptor 4","ui":"D051197","reg":"0"},{"n":"Fibroblast Growth Factors","ui":"D005346","reg":"62031-54-3"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":null,"s2_open_access_landing_url":null,"s2_open_access_license":null,"s2_open_access_status":null,"pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Rationale: Hepatocellular carcinoma (HCC) has been increasingly recognized in nonalcoholic steatohepatitis (NASH) patients. Fibroblast growth factor 21 (FGF21) is reported to prevent NASH and delay HCC development. In this study, the effects of FGF21 on NASH progression and NASH-HCC transition and the potential mechanism(s) were investigated. Methods: NASH models and NASH-HCC models were established in FGF21Knockout (KO) mice to evaluate NASH-HCC transition. IL-17A signaling was investigated in the isolated hepatic parenchymal cells, splenocytes, and hepatocyte and HCC cell lines. Results: Lack of FGF21 caused significant up-regulation of the hepatocyte-derived IL-17A via Toll-like receptor 4 (TLR4) and NF-κB signaling. Restoration of FGF21 alleviated the high NAFLD activity score (NAS) and attenuated the TLR4-triggered hepatocyte-IL-17A expression. The HCC nodule number and tumor size were significantly alleviated by treatments of anti-IL-17A antibody. Conclusion: This study revealed a novel anti-inflammatory mechanism of FGF21 via inhibiting the hepatocyte-TLR4-IL-17A signaling in NASH-HCC models. 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