Ethanol Regulation of Adiponectin and its Signaling

乙醇对脂联素及其信号传导的调节

基本信息

批准号：
9753069
负责人：
MIN YOU
金额：
$ 35.1万
依托单位：
NORTHEAST OHIO MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753069
关键词：
Adipocytes Adipose tissue Alcoholic Liver Diseases Alcoholic liver damage Alcoholic steatohepatitis Alcohols Bile Acids Bile fluid Biochemical Cell Culture Techniques Cells Cirrhosis Clinical Collaborations Development Endocrine Ethanol Event FGF19 gene Fibroblast Growth Factor Fibrosis Grant Hepatic Hepatocyte Homologous Gene Hormones Human Impairment In Vitro Inflammation Inflammatory Response Intestines Knowledge LCN2 gene Laboratories Lipids Liver Liver Failure Mediating Metabolism Modeling Molecular Mus Nutritional Ohio Organ Pathogenesis Patients Pharmacology Play Primary carcinoma of the liver cells Public Health Reagent Regulation Research Risk Factors Rodent Role Sampling Signal Pathway Signal Transduction Steatohepatitis Testing Therapeutic Intervention Work adiponectin alcohol effect alcohol exposure design ileum liver injury mouse model new therapeutic target nonalcoholic steatohepatitis novel novel therapeutics pre-clinical problem drinker protective effect receptor response

项目摘要

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.

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。大量证据表明 ALD（酒精性脂肪性肝炎）的早期阶段是由器官串扰驱动的，缺乏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的了解该提案是一项名为“ALD”的竞争性延续性资助。 “脂联素的乙醇调节及其信号传导”我们的小组最近研究了其根本原因。通过确定乙醇的新靶点来研究乙醇介导的脂联素信号传导损伤机制我们发现，成纤维细胞生长因子 (FGF) 15（人类同源物，FGF19）是一种回肠源性激素。脂联素-FGF15/19 轴失调和脂联素-FGF15/19 信号传导受损与更重要的是，脂联素-FGF15/19 轴赋予啮齿动物和人类酒精性脂肪肝炎的作用。通过微调脂肪-肠-肝脏串扰来防止乙醇引起的肝损伤因此，当前的更新提案将检验一个新颖且令人兴奋的中心假设，即脂联素-FGF15/19 轴在酒精性脂肪性肝炎的发展中起着关键作用，我们将继续研究这一中心假设。通过三个互补的目标，在目标 1 中，我们将研究脂联素-FGF15/19 轴在在目标 2 中，我们将剖析乙醇的作用机制。损害培养的肝细胞和小鼠肝脏中的脂联素-FGF15/19 信号传导。在目标 3 中，我们将进行研究。乙醇下调培养肠细胞和小鼠 FGF15/19 的潜在机制我们将利用细胞培养和遗传或生物化学方法。腺病毒修饰的小鼠模型来剖析介导乙醇作用的分子和细胞事件脂联素-FGF15/19 轴及其信号传导旨在增强。或优化脂联素-FGF15/19轴可能会在管理和治疗方面提供新的治疗策略治疗人类酒精性脂肪性肝炎。