PROJECT SUMMARY The prevalence of cirrhosis and decompensated liver disease has doubled, whereas the prevalence of hepatocellular carcinoma (HCC) has increased 10-fold in the veteran population. Worldwide, HCC has emerged as a major cause of cancer-related death. There is an urgent need to further understand HCC pathogenesis and discover new biomarkers that could accurately predict HCC development in patients with chronic liver diseases, so that we can provide better and more effective strategies for HCC prevention and/or treatment in veteran population. Bile acids (BAs) are well known to be cytotoxic due to their detergent-like properties and overt BAs promote HCC development. In humans, increased levels of secondary BAs, especially deoxycholic acid, is associated with the development of HCC in veteran patients with cirrhosis. BA homeostasis is tightly regulated by farnexoid X receptor (FXR). FXR expression and function are reduced in patients with HCC, and FXR knockout (KO) mice develop spontaneous HCC. FXR suppresses BA levels mainly by fibroblast growth factor 15 (FGF15; FGF19 in humans) mediated gut liver crosstalk and by promoting BA enterohepatic circulation. FGF15/19 emerges to be critical endocrine hormones to suppress BA synthesis, promote liver regeneration and regulate energy homeostasis. Long-term overexpression of FGF15 in vivo (Fgf15 transgenic-Tg mice) results in reduced growth hormone (GH) signaling in the liver and GH signaling is involved in cell proliferation and HCC formation. In this proposal, we will determine the mechanisms by which long-term FGF15 overexpression protects the liver from HCC development in FXR KO mice. Using a novel mouse model we generated, Fgf15 Tg mice, and the newly generated FXR KO/Fgf15 Tg mice, we provided preliminary data showing that FGF15 overexpression completely protected FXR KO mice from developing spontaneous HCC. In addition, overexpression of FGF15 led to a marked reduction in BA levels and GH signaling. Based on these compelling preliminary data, we generate a novel hypothesis: overexpression of FGF15 prevents HCC development through two interactive mechanisms: suppression of BA levels and reduction of GH signaling to reduce cell injury and cell proliferation. This novel hypothesis will be tested in two independent but related specific aims. Aim 1. Determine to what extent reduction of BAs is the mechanism for suppressing HCC development in cholestasis mouse models. Aim 2. Determine the extent of GH signal blockage, and to what extent the reduced GH signal in the Fgf15 Tg mice prevents HCC development. This proposal is highly innovative because we will provide a profound understanding of the molecular mechanisms by which endocrine FGF15 collectively suppresses BA levels and GH signaling, which can markedly prevent HCC development during cholestasis. It is also very technically innovative due to the unique and novel animal models we have generated for in vivo studies. Furthermore, we will p...