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，也是酒精性肝病的主要危险因素。 晚期肝损伤，包括纤维化/肝硬化、肝细胞癌和肝功能衰竭。尽管有大量 大量证据表明ALD的早期阶段，酒精性脂肪性肝炎，是由器官串扰驱动的， 缺乏对器官间串扰内分泌协调因子及其在酒精性脂肪性肝炎中作用的认识 阻碍了ALD研究的进展。该提案是赠款的竞争性延续， “乙醇调节脂联素及其信号传导”.我们小组最近调查了 通过确定乙醇的新靶点，探讨乙醇介导的脂联素信号转导障碍的机制 作用，成纤维细胞生长因子（FGF）15（人同系物，FGF 19），一种回肠衍生激素。我们发现 脂联素-FGF 15/19轴失调和脂联素-FGF 15/19信号转导受损与 酒精性脂肪性肝炎在啮齿动物和人类中的作用。更重要的是，脂联素-FGF 15/19轴赋予 通过微调脂肪-肠-肝串扰防止乙醇诱导的肝损伤。因此，我们认为， 目前的更新建议将检验一个新的和令人兴奋的中心假设，脂联素-FGF 15/19 轴在酒精性脂肪性肝炎的发展中起着关键作用。这一中心假设将继续下去 三个互补的目标。在目的1中，我们将研究脂联素-FGF 15/19轴在细胞凋亡中的作用。 小鼠酒精性脂肪性肝炎的发展。在目标2中，我们将剖析乙醇的作用机制 在培养的肝细胞和小鼠肝脏中损害脂联素-FGF 15/19信号传导。在目标3中，我们将研究 乙醇在培养的肠细胞和小鼠中下调FGF 15/19的潜在机制 回肠我们将利用分子，细胞和生物化学方法与细胞培养和遗传或 腺病毒修饰的小鼠模型，以剖析介导乙醇作用的分子和细胞事件 在脂联素-FGF 15/19轴上，它的信号。药理学或营养学试剂，旨在增强 或优化脂联素-FGF 15/19轴可能在治疗和治疗中提供新的治疗策略， 治疗人酒精性脂肪性肝炎。

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.