Project 1 - Yan Li, PhD

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Non-alcoholic steatohepatitis (NASH), a potential precursor of hepatocellular carcinoma (HCC), currently has no FDA-approved treatment. Recent studies of fibroblast growth factor (FGF)19 and FGF21 on metabolism suggest that endocrine FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic condi- tions, including NASH. The Pegylated FGF21 (MS-986036) and FGF19 agonist (NGM282) have been studied in clinical phase II trials. Our preliminary studies show that the lack of FGF21 accelerates steatohepatities pro- gression and HCC transformation. Overexpression of FGF19/FGF receptor 4 significantly correlated with epithe- lial cell adhesion molecule (EpCAM) as a marker of hepatic cancer stem cells within the fatty liver-steatosis- cirrhosis-HCC sequence in patients. Recent studies indicated that FGF21 down-regulates the Th17-IL-17 axis, suppresses NF-κB but activates p53 pathways, which are the critical anti-cancer mechanism(s). However, there is no evidence demonstrating the specific anticancer effect of FGF21 on the NASH associated HCC. It is also unknown whether FGF21 could negatively affect the Th17-IL-17 axis and the carcinogenetic signaling to abolish the carcinogenetic transformation from NASH to HCC. Our central hypothesis is that FGF21 and FGF15/19 prevent NASH-HCC through, in turn, controlling lipolysis, clearing excessive FFAs, and inhibiting the IL- 17A signaling mediated inflammation and carcinogenesis. The hypothesis will be tested in the following Specific Aims. Aim 1: Investigate lipid metabolic disorder and IL-17A mediated inflammation during NASH-HCC transition. Establishing NASH-HCC mice to, 1) determine FFA pools (plasma, adipose, liver and feces) and FA metabolites by metabolomics; 2) determine metabolic enzymes and components of IL-17A signaling by targeting proteomics. Aim 2: Evaluate the efficacy of FGF21 (LY2405319) and FGF19 (NGM282) against NASH-HCC transition. Administrating LY2405319/NGM282 in NASH-HCC mice to, 1) evaluate NASH score, HCC incidence, hepatic injury and HCC lesion; 3) determine IL-17A-mediated inflammation/carcinogenesis and tumor-initiating cells. Aim 3: Explore the preventive mechanism(s) of FGF21/FGF15/19 against NASH-HCC transition. Repro- ducing NASH-HCC in FGF21 knockout (KO), FGF15KO and IL-17A mutation mice to investigate the feedback loop of FGF21/FGF15/19-IL-17A on molecular target(s) linking to carcinogenetic pathways. The importance of this proposal is: 1) to explore pharmacological use of FGF21/FGF15/19 against the NASH-HCC transition; and 2) to reveal therapeutic targets and mechanism(s), especially the IL-17 signaling linked carcinogenetic pathways, during NASH-HCC transition.