Role of Intestinal Bile Acid Signaling in Liver Diseases

肠胆汁酸信号在肝脏疾病中的作用

• 批准号: 10257976
• 负责人: GRACE L GUO
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10257976
• 关键词: Alcoholic Liver Diseases; Animal Model; Animals; Apoptosis; Automobile Driving; Bile Acid Biosynthesis Pathway; Bile Acids; Biological Markers; Cancer Etiology; Cell Proliferation; Cessation of life; Cholestasis; Cholic Acids; Cirrhosis; Data; Deoxycholic Acid; Detergents; Development; Early Diagnosis; Endocrine; Enterohepatic Circulation; Event; FGF19 gene; Fibroblast Growth Factor; Future; Goals; Growth; Health Benefit; Homeostasis; Hormones; Human; Intestines; Knock-out; Knockout Mice; Liver; Liver Regeneration; Liver diseases; Mediating; Medical; Molecular; Mus; Pathogenesis; Pathology; Pathway interactions; Patients; Physiology; Play; Prevalence; Prevention; Primary carcinoma of the liver cells; Property; Research; Rodent; Role; Signal Transduction; Somatotropin; Testing; Time; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; Veterans; base; cell injury; chronic liver disease; cytotoxic; diagnostic biomarker; drug induced liver injury; effective therapy; hormonal signals; in vivo; innovation; military veteran; mouse model; non-alcoholic fatty liver disease; novel; overexpression; patient population; prevent; receptor; receptor expression; receptor function; tumor

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.

项目概要 肝硬化和失代偿性肝病的患病率翻了一番，而 退伍军人中的肝细胞癌 (HCC) 增加了 10 倍。在全球范围内，HCC 已 已成为癌症相关死亡的主要原因。迫切需要进一步了解 HCC 发病机制并发现可以准确预测患者 HCC 发展的新生物标志物 慢性肝病，以便我们能够提供更好、更有效的 HCC 预防和/或 退伍军人群体的治疗。众所周知，胆汁酸 (BA) 具有细胞毒性，因为它们具有类似去垢剂的性质 属性和明显的 BA 促进 HCC 的发展。在人类中，次级 BA 水平增加， 尤其是脱氧胆酸，与退伍军人肝硬化患者的 HCC 发展相关。学士 体内平衡受到 Farnexoid X 受体 (FXR) 的严格调节。 FXR 表达和功能减少 HCC 患者和 FXR 敲除 (KO) 小鼠会发展为自发性 HCC。 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）介导的肠肝串扰以及促进 BA 肠肝循环。 FGF15/19 成为抑制 BA 合成的关键内分泌激素， 促进肝脏再生并调节能量稳态。 FGF15体内长期过表达 （Fgf15 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 信号传导减弱 参与细胞增殖和HCC形成。在本提案中，我们将确定以下机制： 长期 FGF15 过度表达可保护 FXR KO 小鼠的肝脏免受 HCC 的发展。使用小说 我们提供了我们生成的小鼠模型、Fgf15 Tg 小鼠和新生成的 FXR KO/Fgf15 Tg 小鼠 初步数据显示 FGF15 过表达完全保护 FXR KO 小鼠免于发育 自发性肝癌。此外，FGF15的过度表达导致BA水平和GH水平显着降低。 发信号。基于这些令人信服的初步数据，我们提出了一个新的假设：过度表达 FGF15 通过两种相互作用机制预防 HCC 发展：抑制 BA 水平和 减少 GH 信号传导以减少细胞损伤和细胞增殖。这一新颖的假设将在两个方面进行检验 独立但相关的具体目标。目标 1. 确定 BA 的减少程度是 抑制胆汁淤积小鼠模型中 HCC 的发展。目标 2. 确定 GH 信号的范围 阻断，以及 Fgf15 Tg 小鼠中 GH 信号减少在多大程度上阻止了 HCC 的发展。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FGF15共同抑制BA水平和GH信号传导，可以显着预防 胆汁淤积期间发生 HCC。由于动物独特新颖，在技术上也非常创新 我们为体内研究生成的模型。此外，我们还将提供对 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 因为人类和啮齿类动物在肝病发展过程中具有相似的 BA 途径。我们相信，这 研究将为人类肝癌的预防、早期诊断和治疗提供科学依据 肝硬化退伍军人患者的未来发展。