Obesity has become a major risk factor for a number of human diseases, including cancer. Amongst different types of malignancies, obesity appears to have the highest association-rate with hepatocellular carcinoma (HCC), the dominant form of primary liver cancer. Obesity-induced sterile inflammation is the key switch mediating the transition from hepatic steatosis to steatohepatitis (non-alcoholic steatohepatitis, NASH) and HCC. However, the molecular mechanism underlying obesity-induced hepatic inflammation remains poorly understood. We show that fat accumulation increases liver damage and release of DAMP (damage-associated molecular patterns) from dying hepatocytes, to amplify inflammation and accelerate hepatic disease progression. These DAMP induce mitochondrial reactive oxygen species (mtROS) in macrophages, which direct inflammatory cytokine/chemokine production in a manner that requires activation of a calcium permeable channel, TRPM2 (transient receptor potential melastatin 2). Blockade of mtROS generation, removal of extracellular calcium or ablation of TRPM2 expression in macrophages abolished DAMP-induced inflammatory cytokine/chemokine production, suggesting that a “mtROS-TRPM2” pathway drives DAMP-induced inflammation. Moreover, we identified HMGB1 as the key DAMP released from lipid-damaged hepatocytes. By using HMGB1 neutralizing antibody, we found it suppressed HMGB1 expression in the liver of MUP-uPA mice (an animal model for human NASH), and markedly attenuated liver damage, accumulation of lipid droplets, inflammation, and fibrosis, which represent typical features of human NASH. These results also suggest that HMGB1 is a key component of a vicious autoregulatory cycle triggered by HFD consumption, that mains ER stress and liver inflammation, as well as elevated HMGB1 expression and release.
Citation Format: Zhenyu Zhong, Atsushi Umemura, Shuang Liang, Michael Karin. Identification of key immune regulators that control obesity-induced liver inflammation and diseases. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A138.
- ©2016 American Association for Cancer Research.