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：
8214193
负责人：
MIN YOU
金额：
$ 32.89万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214193
关键词：
ADD-1 protein Acetylation Adipocytes Adipose tissue Affect Alcoholic Fatty Liver Animal Model Animals Biochemical CD36 gene Cell Culture Techniques Chronic Cirrhosis Complex Deacetylase Development Dietary Factors Down-Regulation Ethanol Ethanol dependence Event Fibrosis Funding Grant Hepatic Human Impairment Injury Knowledge Laboratories Lead Length Lipids Liver Liver diseases Malonyl Coenzyme A Mediating Messenger RNA Molecular Mus Nuclear Pathogenesis Peroxisome Proliferator-Activated Receptors Play Production Property Protein Secretion Proteins Recombinants Regulation Resveratrol Risk Factors Rodent Model Role SRE-1 binding protein STK11 gene Signal Pathway Signal Transduction Steatohepatitis Therapeutic Work adipokines adiponectin alcohol effect alcohol exposure feeding lipid biosynthesis lipine new therapeutic target novel novel therapeutics overexpression oxidation prevent receptor expression treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Alcoholic fatty liver disease (AFLD) is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. During the last grant period, we and several other groups have discovered that the development of AFLD in several rodent models is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. While the role of adiponectin and its hepatic signaling has been firmly established in the development of AFLD, the cellular and molecular mechanisms whereby ethanol inhibits the expression and production of adiponectin in adipose tissue and impairs adiponectin-mediated signaling in liver remain largely unknown. Therefore, this current competitive renewal proposal focuses specifically and exclusively on the molecular mechanisms of ethanol-induced inhibition of adipose adiponectin expression and impairment of hepatic adiponectin signaling by examining novel and exciting hypotheses that two important adipose transcriptional regulators, FoxO1 and Lipin-1, may be involved in ethanol-dependent regulation of adiponectin, and that the inhibitory effect of ethanol on adiponectin via these two molecules may result partially from ethanol inhibition of SIRT1, an NAD(+)-dependent class III protein deacetylase, and more generally, SIRT1 may represent a central target for the action of adiponectin and ethanol both in the adipose tissue and in the liver. The Specific Aims of the proposal are to: 1) Investigate the roles of FoxO1, Lipin-1 and SIRT1 in ethanol-mediated down regulation of adiponectin in mouse adipose tissue; 2) Identify underlying mechanisms by which ethanol impairs the SIRT1-adiponectin axis via FoxO1 or Lipin-1 in cultured adipocytes; 3) Investigate the mechanisms through which ethanol impairs hepatic adiponectin-SIRT1 signaling. We will utilize state-of-the-art molecular, cellular and biochemical approaches with cell culture and animal models to dissect the signaling events mediating the action of ethanol on adiponectin and its hepatic signaling. Since effects of ethanol on SIRT1 and adiponectin are highly regulated by dietary factors and pharmacological agents, these studies may lead to novel therapeutic strategies for the treatment of human AFLD and possibly steatohepatitis. PUBLIC HEALTH RELEVANCE: Adiponectin plays a vital role in the development of alcoholic fatty liver disease. This renewal application will study the molecular mechanisms by which ethanol inhibits adipose-derived adiponectin expression and impairs its hepatic signaling. This study will increase our knowledge of the pathogenesis and therapeutics for treatment of human alcoholic fatty liver disease and possibly steatohepatitis.

描述（由申请人提供）：酒精性脂肪肝病（AFLD）是脂肪性肝炎、纤维化和肝硬化等晚期肝损伤的主要危险因素。脂联素是脂肪细胞衍生的脂肪因子之一，具有有效的降脂特性。在上一个资助期间，我们和其他几个小组发现，几种啮齿动物模型中 AFLD 的发生与循环脂联素水平降低、肝脂联素受体表达减少和肝脂联素信号传导受损有关。虽然脂联素及其肝脏信号传导在 AFLD 的发展中的作用已被牢固确立，但乙醇抑制脂肪组织中脂联素的表达和产生并损害肝脏中脂联素介导的信号传导的细胞和分子机制仍然很大程度上未知。因此，当前的竞争性更新提案通过检查两个重要的脂肪转录调节因子 FoxO1 和 Lipin-1 可能可能的新颖且令人兴奋的假设，专门关注乙醇诱导的脂肪脂联素表达抑制和肝脂联素信号传导受损的分子机制。参与脂联素的乙醇依赖性调节，乙醇通过这两个分子对脂联素的抑制作用可能部分来自乙醇对 SIRT1 的抑制，SIRT1 是一种NAD(+)依赖性III类蛋白脱乙酰酶，更一般地说，SIRT1可能代表脂联素和乙醇在脂肪组织和肝脏中作用的中心靶标。该提案的具体目标是：1）研究FoxO1、Lipin-1和SIRT1在乙醇介导的小鼠脂肪组织中脂联素下调中的作用； 2) 确定乙醇通过 FoxO1 或 Lipin-1 在培养的脂肪细胞中损害 SIRT1-脂联素轴的潜在机制； 3) 研究乙醇损害肝脂联素-SIRT1 信号传导的机制。我们将利用最先进的分子、细胞和生化方法以及细胞培养和动物模型来剖析介导乙醇对脂联素及其肝脏信号传导作用的信号传导事件。由于乙醇对 SIRT1 和脂联素的影响受到饮食因素和药物的高度调节，因此这些研究可能会带来治疗人类 AFLD 和可能的脂肪性肝炎的新治疗策略。公共卫生相关性：脂联素在酒精性脂肪肝疾病的发展中起着至关重要的作用。这项更新应用将研究乙醇抑制脂肪源性脂联素表达并损害其肝脏信号传导的分子机制。这项研究将增加我们对人类酒精性脂肪肝病和可能的脂肪性肝炎的发病机制和治疗方法的了解。