Role of Intestinal Bile Acid Signaling in Liver Diseases

项目摘要 肝硬化和失代偿性肝病的患病率增加了一倍，而 肝细胞癌（HCC）在退伍军人中增加了10倍。在全球范围内，HCC 成为癌症相关死亡的主要原因。迫切需要进一步了解HCC 发病机制，并发现新的生物标志物，可以准确地预测肝癌患者的发展， 慢性肝病，以便我们可以提供更好，更有效的HCC预防策略和/或 治疗老年人。众所周知，胆汁酸（BA）具有细胞毒性，因为它们具有去污剂样作用。 属性和显性BA促进HCC发展。在人类中，二级BA水平的增加， 尤其是脱氧胆酸，与肝硬化退伍军人患者HCC的发生有关。BA 体内平衡受类纤维素X受体（FXR）的严格调节。FXR的表达和功能降低， HCC患者和FXR敲除（KO）小鼠发生自发性HCC。FXR抑制BA水平 主要通过成纤维细胞生长因子15（FGF 15;人中的FGF 19）介导的肠肝串扰和通过促进 BA肠肝循环。FGF 15/19是抑制BA合成的关键内分泌激素， 促进肝脏再生和调节能量平衡。FGF 15在体内的长期过表达 （Fgf 15转基因-Tg小鼠）导致肝脏中生长激素（GH）信号传导减少，并且GH信号传导被抑制。 参与细胞增殖和HCC形成。在本提案中，我们将确定 长期FGF 15过表达在FXR KO小鼠中保护肝脏免于HCC发展。使用一种新 我们生成的小鼠模型Fgf 15 Tg小鼠和新生成的FXR KO/Fgf 15 Tg小鼠，我们提供了 初步数据显示，FGF 15过表达完全保护FXR KO小鼠免于发展成 自发性肝癌。此外，FGF 15的过度表达导致BA水平和GH水平的显著降低。 信号基于这些令人信服的初步数据，我们提出了一个新的假设： FGF 15通过两种相互作用机制防止HCC发展：抑制BA水平， 减少GH信号传导以减少细胞损伤和细胞增殖。这一新的假设将在两个测试 独立但相关的具体目标。目标1.确定BA减少的程度是 在胆汁淤积小鼠模型中抑制HCC发展。目标二。确定GH信号的范围 阻断，以及在Fgf 15 Tg小鼠中降低的GH信号在多大程度上防止HCC发展。这 该提案具有高度创新性，因为我们将提供对分子机制的深刻理解 通过内分泌FGF 15共同抑制BA水平和GH信号传导， 胆汁淤积期间发生HCC。它也是非常技术创新，由于独特和新颖的动物 我们为体内研究建立的模型。此外，我们还将深入了解 BA稳态、肝脏生长和HCC发展的机制。这项研究将与人类高度相关 因为人类和啮齿动物在肝病发展中共享相似的BA途径。我们认为这 为肝癌的预防、早期诊断和治疗提供科学依据 未来肝硬化退伍军人患者的发展。

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.