Project 1 - Yan Li, PhD

非酒精性脂肪性肝炎(NASH)是肝细胞癌(HCC)的潜在先兆，目前没有 FDA批准的治疗方法。成纤维细胞生长因子19和成纤维细胞生长因子21对代谢的最新研究提示 内分泌FGFs及其衍生物作为治疗新陈代谢疾病的新疗法具有巨大的潜力。 包括纳什在内的所有人。聚乙二醇化成纤维细胞生长因子21(MS-986036)和成纤维细胞生长因子19激动剂(NGM282)的研究 在临床II期试验中。我们的初步研究表明，缺乏FGF21会加速脂肪性肝炎的进展。 分化与肝细胞癌的转化。FGF19/成纤维细胞生长因子受体4的过度表达与瘢痕疙瘩显著相关 肝细胞黏附分子(EpCAM)作为脂肪肝-脂肪变性内肝癌干细胞的标志物 患者中的肝硬变-肝细胞癌序列。最近的研究表明，FGF21下调Th17-IL-17轴， 抑制核因子-κB，但激活P53通路，这是关键的抗癌机制(S)。然而，在那里 目前尚无证据表明FGF21对NASH相关肝细胞癌有特异性抗癌作用。它也是 未知FGF21是否会对Th17-IL-17轴和致癌信号产生负面影响 NASH向肝癌的致癌转化。我们的中心假设是FGF21和FGF15/19 进而通过控制脂解、清除过量的FFA和抑制IL-2来预防NASH-HCC。 17A信号介导炎症和癌变。这一假设将在以下方面得到检验 明确的目标。目的1：探讨NASH-肝细胞癌中脂代谢紊乱和IL-17A介导的炎症反应 过渡。建立NASH-HCC小鼠，1)测定FFA池(血浆、脂肪、肝脏和粪便)和FA 代谢组学；2)靶向测定代谢酶和IL-17A信号成分 蛋白质组学。目的2：评价FGF21(LY2405319)和FGF19(NGM282)对NASH-HCC的治疗作用 过渡。LY2405319/NGM282在NASH-HCC小鼠体内应用，1)评估NASH评分，肝癌发病率， 肝损伤与肝细胞癌损害；3)IL-17A介导的炎症/癌变及肿瘤的发生 细胞。目的：探讨FGF21/FGF15/19预防NASH向肝癌转化的作用机制(S)。转载- 在FGF21基因敲除(KO)、FGF15KO和IL-17A突变小鼠中诱导NASH-肝癌研究反馈 FGF21/FGF15/19-IL-17A在分子靶点(S)上的环与致癌途径的联系重要的是 这项建议是：1)探索FGF21/FGF15/19在抗NASH-肝癌转化中的药理作用；以及 2)揭示治疗靶点和作用机制(S)，特别是IL-17信号转导致癌途径。 在NASH向肝细胞癌转变过程中。

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.