Ethanol Regulation of Adiponectin and its Signaling

酒精性脂肪性肝炎是酒精性肝病(ALD)的初始阶段，也是 严重的肝脏损伤，包括纤维化/硬化、肝细胞癌和肝功能衰竭。尽管有很大的 大量证据表明，酒精性脂肪性肝炎的早期阶段是由器官串扰引起的， 对器官间串扰内分泌协调器及其在酒精性脂肪性肝炎中的作用缺乏了解 阻碍了ALD研究的进展。这项提案是这笔赠款的竞争性延续，名为 《乙醇对脂联素的调节及其信号转导》。我们的团队最近研究了 乙醇新靶点识别对脂联素信号转导的影响 作用，成纤维细胞生长因子15(人的同系物，FGF19)，一种来自回肠的激素。我们发现了 脂联素-FGF15/19轴异常和脂联素-FGF15/19信号受损与 啮齿动物和人类的酒精性脂肪性肝炎。更重要的是，脂联素-FGF15/19轴赋予 通过微调脂肪-肠道-肝脏串扰来保护乙醇所致的肝损伤。因此， 目前的更新建议将检验一个新的和令人兴奋的中心假设，即脂联素-FGF15/19 AXIS在酒精性脂肪性肝炎的发生发展中起着关键作用。这一中心假设将得到贯彻 三个相辅相成的目标。在目标1中，我们将研究脂联素-FGF15/19轴在血管紧张素转换酶中的作用。 小鼠酒精性脂肪性肝炎的发生发展。在目标2中，我们将剖析乙醇通过 损害培养的肝细胞和小鼠肝脏中的脂联素-FGF15/19信号。在目标3中，我们将调查 乙醇下调培养肠细胞和小鼠肠上皮细胞FGF15/19的机制 回肠。我们将利用分子、细胞和生化方法进行细胞培养，并在基因或 腺病毒修饰的小鼠模型剖析介导乙醇效应的分子和细胞事件 脂联素-FGF15/19轴及其信号转导。药理或营养试剂旨在增强 或优化脂联素-FGF15/19轴可能为新的治疗策略提供管理和 人类酒精性脂肪性肝炎的治疗。

Alcoholic steatohepatitis is the initial stage of alcoholic liver disease (ALD) and a major risk factor for advanced liver injuries, including fibrosis/cirrhosis, hepatocellular carcinoma and liver failure. Despite a large body of evidence suggesting that the early stage of ALD, alcoholic steatohepatitis, is driven by organ crosstalk, lack of knowledge on the inter-organ crosstalk endocrine coordinators and their roles in alcoholic steatohepatitis has hampered the progress of ALD research. This proposal is a competing continuation of the grant, titled “Ethanol Regulation of Adiponectin and It's Signaling". Our group has recently investigated the underlying mechanisms of ethanol-mediated impairment of adiponectin signaling by identifying a new target of ethanol action, fibroblast growth factor (FGF) 15 (human homolog, FGF19), an ileum-derived hormone. We have found that dysregulated adiponectin-FGF15/19 axis and impaired adiponectin-FGF15/19 signaling are associated with alcoholic steatohepatitis in rodents and humans. More importantly, adiponectin-FGF15/19 axis confers protection against ethanol-induced liver damage via fine-tuning the adipose-intestine-liver crosstalk. Therefore, this current renewal proposal will examine a novel and exciting central hypothesis that adiponectin-FGF15/19 axis plays a pivotal role in the development of alcoholic steatohepatitis. This central hypothesis will be pursued through three complementary aims. In Aim 1, we will investigate the role of adiponectin-FGF15/19 axis in the development of alcoholic steatohepatitis in mice. In Aim 2, we will dissect the mechanisms through which ethanol impairs adiponectin-FGF15/19 signaling in cultured hepatocytes and in mouse livers. In Aim 3, we will investigate the underlying mechanisms by which ethanol down-regulates FGF15/19 in cultured intestinal cells and in mouse ileum. We will utilize molecular, cellular, and biochemical approaches with cell culture and in genetically or adenoviral modified mouse models to dissect the molecular and cellular events mediating the effects of ethanol on adiponectin-FGF15/19 axis and it's signaling. Pharmacological or nutritional reagents designed to enhancing or optimizing the adiponectin-FGF15/19 axis may serve novel therapeutic strategies in the management and treatment of human alcoholic steatohepatitis.