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; 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.

项目摘要 肝硬化和代偿肝脏疾病的患病率增加了一倍 肝细胞癌（HCC）在退伍军人口中增加了10倍。全球，HCC拥有 成为癌症相关死亡的主要原因。迫切需要进一步了解HCC 发病机理并发现可以准确预测患有HCC的新生物标志物 慢性肝病，以便我们可以为预防HCC提供更好，更有效的策略和/或 在退伍军人人口中进行治疗。胆汁酸（BAS）众所周知，由于其清洁剂样而具有细胞毒性 属性和明显的BAS促进HCC的开发。在人类中，次级BAS的水平增加， 尤其是脱氧胆酸与肝硬化退伍军人患者的HCC发展有关。 BA 稳态受到Farnexoid X受体（FXR）的严格调节。 FXR的表达和功能降低 HCC和FXR敲除（KO）小鼠患者会自发HCC。 FXR抑制BA水平 主要由成纤维细胞生长因子15（FGF15；人类中的FGF19）介导的肠道肝脏串扰，并促进 BA肠肝循环。 FGF15/19出现是抑制BA合成的关键内分泌激素， 促进肝脏再生并调节能量稳态。体内FGF15的长期过表达 （FGF15转基因-TG小鼠）导致肝脏中的生长激素（GH）信号降低，GH信号为 参与细胞增殖和HCC形成。在此提案中，我们将确定 长期FGF15过表达可保护肝脏免受FXR KO小鼠的HCC发育。使用小说 我们生成的鼠标模型，FGF15 TG小鼠和新生成的FXR KO/FGF15 TG小鼠，我们提供了 初步数据表明，FGF15过表达完全保护FXR KO小鼠免于发展 自发的HCC。此外，FGF15的过表达导致BA水平明显降低和GH 信号。基于这些引人入胜的初步数据，我们产生了一个新的假设： FGF15通过两种互动机制来防止HCC开发：抑制BA水平和 还原GH信号传导以减少细胞损伤和细胞增殖。这个新颖的假设将在两个中进行检验 独立但相关的特定目的。目标1。确定BAS的降低程度是 抑制胆汁淤积小鼠模型中的HCC发育。目标2。确定GH信号的程度 阻塞，以及FGF15 TG小鼠中的GH信号在多大程度上阻止了HCC的发育。这 提案具有很高的创新性，因为我们将对分子机制有深刻的了解 内分泌FGF15共同抑制BA级别和GH信号，这可以明显防止 胆汁淤积期间的HCC开发。由于独特而新颖的动物，它在技术上也是非常创新的 我们为体内研究生成的模型。此外，我们将对 BA稳态，肝脏生长和HCC发育的机制。这项研究将是高度人性的 因为人类和啮齿动物在肝病发展中具有相似的BA途径。我们相信这个 研究将有助于为人类HCC的预防，早期诊断和治疗提供科学基础 未来肝硬化退伍军人患者的发展。