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

Publication date: 11 July 2016
Source:Cancer Cell, Volume 30, Issue 1
Author(s): Ana L. Gomes, Ana Teijeiro, Stefan Burén, Krishna S. Tummala, Mahmut Yilmaz, Ari Waisman, Jean-Philippe Theurillat, Cristian Perna, Nabil Djouder
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.

Graphical abstract

Teaser

Gomes et al. show that excess nutrients lead to URI-dependent DNA damage in hepatocytes, triggering inflammation via Th17 cells and IL-17A. Suppression of Th17 cell differentiation or blocking IL-17A signaling prevents non-alcoholic steatohepatitis and subsequent hepatocellular carcinoma.


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