Role of Intestinal Bile Acid Signaling in Liver Diseases

项目总结 肝硬变和失代偿性肝病的患病率翻了一番，而 在退伍军人中，肝细胞癌(肝细胞癌)的发病率增加了10倍。在世界范围内，肝癌已经 成为癌症相关死亡的主要原因。迫切需要进一步了解肝细胞癌 发病机制和发现新的生物标志物可以准确预测肝癌的发展 慢性肝病，以便为肝癌的预防和/或提供更好和更有效的策略 在退伍军人群体中进行治疗。众所周知，胆汁酸(BA)具有细胞毒性，因为它们类似洗涤剂。 属性和显性基础促进了肝细胞癌的发展。在人类中，次级bas水平增加， 尤其是脱氧胆酸，与老年肝硬变患者肝细胞癌的发生有关。基数 动态平衡受到法尼索X受体(FXR)的严格调控。FXR的表达和功能在 肝癌患者和FXR基因敲除(KO)小鼠发生自发性肝癌。FXR抑制BA水平 主要通过成纤维细胞生长因子15(FGF15；人类中的FGF19)介导的肠肝串扰和促进 BA肠-肝循环。FGF15/19是抑制BA合成的关键内分泌激素， 促进肝脏再生，调节能量平衡。成纤维细胞生长因子15在体内的长期过表达 (Fgf15转基因-TG小鼠)导致肝脏中生长激素(GH)信号的减少，GH信号是 参与细胞增殖和肝细胞癌的形成。在这项提案中，我们将确定通过哪些机制 在FXR KO小鼠中，长期过表达FGF15可以保护肝脏免受肝癌的发展。用一本小说 我们建立的小鼠模型，Fgf15 TG小鼠，以及新生成的FXR KO/Fgf15 TG小鼠，我们提供 初步数据显示FGF15过表达完全保护FXR KO小鼠发育 自发性肝癌。此外，FGF15的过度表达导致BA水平和GH水平显著下降 发信号。基于这些令人信服的初步数据，我们产生了一个新的假设：过度表达 FGF15通过两种相互作用机制预防肝癌的发生：抑制BA水平和 减少生长激素信号转导，减轻细胞损伤和细胞增殖。这一新的假设将分两个阶段进行检验 独立但相关的具体目标。目标1.确定在多大程度上降低BAS是 抑制胆汁淤积症小鼠肝癌的发展。目的2.确定生长激素信号的幅度 阻断，以及Fgf15转基因小鼠中生长激素信号的减少在多大程度上阻止了肝癌的发展。这 该提议具有很高的创新性，因为我们将提供对分子机制的深刻理解 通过内分泌FGF15共同抑制BA水平和GH信号，可以显著防止 肝细胞癌在胆汁淤积期的发展。由于独特而新颖的动物，它在技术上也非常创新 我们为活体研究建立的模型。此外，我们还将深入了解 BA动态平衡、肝脏生长和肝细胞癌发生的机制这项研究将与人类高度相关 因为人类和啮齿动物在肝脏疾病的发展过程中有着相似的BA途径。我们相信这一点 本研究将为人类肝癌的预防、早期诊断和治疗提供科学依据 肝硬变老兵未来的发展。

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 provide profound understanding of the mechanisms of BA homeostasis, liver growth and HCC development. This study will be highly human relevant because humans and rodents share similar BA pathways in liver disease development. We believe that this study will help to provide scientific basis for prevention, early diagnosis, and treatment of human HCC development in cirrhotic veteran patients in the future.