Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. With a steady increase of obesity epidemic in the United States, the incidence of obesity-associated HCC has skyrocketed. Obesity-induced HCC is the terminal manifestation of non-alcoholic fatty liver disease (NAFLD) - a spectrum of chronic liver diseases originating from benign fatty liver that can progress into nonalcoholic steatohepatitis (NASH) and eventually HCC. Obesity induces lipid buildup in hepatocyte, resulting in cell death and subsequent release of danger molecules to ignite inflammation. Although previous studies have demonstrated that chronic liver inflammation is a "stage-setting" st...

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. With a steady increase of obesity epidemic in the United States, the incidence of obesity-associated HCC has skyrocketed. Obesity-induced HCC is the terminal manifestation of non-alcoholic fatty liver disease (NAFLD) - a spectrum of chronic liver diseases originating from benign fatty liver that can progress into nonalcoholic steatohepatitis (NASH) and eventually HCC. Obesity induces lipid buildup in hepatocyte, resulting in cell death and subsequent release of danger molecules to ignite inflammation. Although previous studies have demonstrated that chronic liver inflammation is a "stage-setting" step for HCC, little is known about how obesity results in chronic liver inflammation in the first place. To counteract the accumulation of dying cells, the host immune system has assembled an army of phagocytes (mostly macrophages) that serve as sentinels by recognizing and removing dead cells - also known as "efferocytosis", thereby limiting inflammation. However, it is unclear whether macrophage efferocytosis plays a role in the pathogenesis of obesity-induced HCC. With a laser focus on dissecting the role of TREM2-mediated efferocytosis in the pathogenesis of obesity-induced HCC, the short-term outcome of our proposal is that it will be paradigm-shifting through illuminating previously unrecognized molecular mechanisms that could solve a long-standing question, which is how obesity leads to chronic liver inflammation. Moreover, if our hypothesis is proven correct, it will also guide the development of new preventive strategies and early detection methods to alleviate the burden of liver cancer in obese population. The long-term outcome of this project is that it will break new ground for liver cancer research and thereby conceptually advance our current understanding regarding how obesity promotes liver cancer development.

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