title: Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma.
abstract: Obesity increases hepatocellular carcinoma (HCC) risks via unknown mediators. We report that hepatic unconventional prefoldin RPB5 interactor (URI) couples nutrient surpluses to inflammation and non-alcoholic steatohepatitis (NASH), a common cause of HCC. URI-induced DNA damage in hepatocytes triggers inflammation via T helper 17 (Th17) lymphocytes and interleukin 17A (IL-17A). This induces white adipose tissue neutrophil infiltration mediating insulin resistance (IR) and fatty acid release, stored in liver as triglycerides, causing NASH. NASH and subsequently HCC are prevented by pharmacological suppression of Th17 cell differentiation, IL-17A blocking antibodies, and genetic ablation of the IL-17A receptor in myeloid cells. Human hepatitis, fatty liver, and viral hepatitis-associated HCC exhibit increased IL-17A correlating positively with steatosis. IL-17A blockers may prevent IR, NASH, and HCC in high-risk patients.
authors.affiliation: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Gomes
authors.affiliation: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Teijeiro
authors.affiliation: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors.forename: Stefan
authors.initials: S
authors.lastname: Burén
authors.affiliation: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors.forename: Krishna S
authors.initials: KS
authors.lastname: Tummala
authors.affiliation: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Yilmaz
authors.affiliation: Institute for Molecular Medicine, University Medical Center, Johannes Gutenberg University of Mainz, Mainz 55131, Germany.
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Functional Cancer Genomics Group, Institute of Oncology Research (IOR), Bellinzona 6500, Switzerland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Theurillat
authors.affiliation: Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid 28034, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Perna
authors.affiliation: Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain. Electronic address: ndjouder@cnio.es.
authors.forename: Nabil
authors.initials: N
authors.lastname: Djouder
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D004249:DNA Damage; D059305:Diet, High-Fat / Q000009:adverse effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D012097:Repressor Proteins; D058504:Th17 Cells / Q000276:immunology
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C117184:URI1 protein, human