Project Summary Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide, with 5- year survival less than 12%. Paralleling the increased incidence of HCC is the rise of obesity and the related metabolic syndrome including nonalcoholic fatty liver disease (NAFLD), and recent epidemiologic studies directly link NAFLD to HCC. The identification of obesity as a major modifiable risk factor for HCC development highlights the urgency of understanding the underlying mechanisms that drive the linkage of NAFLD and HCC. Our long-term goal is to understand the molecular mechanism underlying obesity related HCC and develop novel therapeutic strategies. The overall objective for this grant is to investigate how nuclear receptor CAR regulates HCC lipid synthesis to promote tumorigenesis and determine whether simultaneously blocking CAR and lipid uptake is effective in obesity related HCC. Our preliminary results demonstrate that suppressing CAR activity via Inverse Agonist (CAR-IA) inhibits mouse HCC growth with normal chow diet, however this tumor inhibition effect can be completely reversed by high fat diet (HFD) feeding. Mechanistically, we found that CAR suppression by CAR-IA inhibits tumor lipid synthesis in both mouse and human HCC. CD36 mediated lipid uptake potentially reverse lipid deprivation condition and growth inhibition caused by CAR-IA in HCC from HFD feeding. These exciting results support our hypothesis that (1) suppressing CAR inhibits normal chow HCC growth through repressing tumor lipid synthesis and (2) blockade of both CAR mediated de novo lipid synthesis and CD36 mediated exogenous lipid uptake will provide synthetic lethality in obesity associated HCC. In Aim 1, we will define the mechanisms by which CAR inhibition represses HCC lipid synthesis and growth. Aim 2 will determine whether lipid uptake blockade sensitizes mouse HCC/HFD to CAR inhibition. Lastly, Aim 3 will define the impact of CAR suppression on normal and obesity related human HCC. Targeting tumor lipid synthesis has opened a promising therapeutic window for many tumors, including HCC. However, strong toxic effects and limited effectiveness of the current lipogenic inhibitors have confounded clinical trials. In contrast, CAR suppression by mouse CAR-IA shows no toxicity in mice and human CAR-IA meclizine is an FDA proved antihistamine drug. Importantly, this proposal integrates the overlapping roles of lipid synthesis and uptake in obesity related HCC. Successful deployment of co-treatment with inhibitors for lipid synthesis and uptake would have a major impact on obesity related HCC.

Project Narrative Epidemiologic studies identify that obesity and the related metabolic syndrome nonalcoholic fatty liver disease (NAFLD) are major risk factors of hepatocellular carcinoma (HCC). The goal of this proposal is to investigate how the nuclear receptor CAR regulates tumor lipid synthesis to promote HCC, and determine whether simultaneously blocking CAR and lipid uptake is therapeutically effective in obesity related HCC. 1