6533b823fe1ef96bd127e0ec

RESEARCH PRODUCT

Metabolic Inflammation-Associated IL-17A Causes Non-alcoholic Steatohepatitis and Hepatocellular Carcinoma

Ana GomesCristian PernaKrishna S. TummalaMahmut Ilker YilmazJean-philippe TheurillatAna TeijeiroNabil DjonderStefan BurénAri Waisman

subject

Male0301 basic medicineCancer ResearchCarcinoma HepatocellularInflammationWhite adipose tissueDiet High-FatMice03 medical and health sciencesNon-alcoholic Fatty Liver DiseasemedicineAnimalsHumansUnconventional prefoldin RPB5 interactorbiologyInterleukin-17Liver NeoplasmsFatty liverIntracellular Signaling Peptides and ProteinsCell Biologymedicine.diseasedigestive system diseasesGene Expression Regulation NeoplasticRepressor Proteins030104 developmental biologyNeutrophil InfiltrationOncologyHepatocellular carcinomaImmunologybiology.proteinTh17 CellsInterleukin 17SteatosisSteatohepatitismedicine.symptomDNA Damage

description

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.

yearjournalcountryeditionlanguage
2016-07-01Cancer Cell
https://doi.org/10.1016/j.ccell.2016.05.020