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：
7264006
负责人：
MIN YOU
金额：
$ 33.44万
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 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7264006
关键词：
2,4-thiazolidinedione 5&apos -AMP-activated protein kinase Adipocytes Adipose tissue Agonist Alcoholic Fatty Liver Animals Binding Cholesterol Chronic Cultured Cells Development Dietary Fatty Acid Energy Metabolism Ethanol Fatty Acids Fatty Liver Gene Expression Hepatic Histology Hormones Lead Length Lipids Liver Liver diseases Maintenance Measures Mediating Mediator of activation protein Membrane Messenger RNA Metabolic Modeling Molecular Molecular Weight Mus Nuclear Nutritional PPAR alpha PPAR gamma Pathway interactions Plasma Plasma Proteins Play Protein Isoforms Proteins Rate Rattus Recombinants Regulation Role SRE-1 binding protein Signal Pathway Signal Transduction Steatohepatitis Testing Thiazolidinediones Triglycerides adiponectin alcohol effect alcohol exposure carbohydrate metabolism cofactor feeding lipid metabolism novel therapeutics oxidation problem drinker protein distribution receptor rosiglitazone transcription factor

项目摘要

DESCRIPTION (provided by applicant): Ethanol causes the development and maintenance of fatty liver by effects on two important liver nuclear transcription factors that are involved in hepatic fatty acid synthesis and oxidation pathways, activation of sterol regulatory element binding protein-1 (SREBP-1), and inhibition of peroxisome proliferators activated receptor alpha (PPARa). Moreover, ethanol effects on these transcription factors are resulted partially from ethanol inhibition of hepatic AMP-activated kinase (AMPK), a key "metabolic switch" controlling pathways of hepatic cholesterol and triglyceride synthesis. Recently, studies have identified AMPK, PPARa and SREBP-1 as the major mediators of the metabolic effect of the newly discovered hormone adiponectin. Adiponectin, a hormone exclusively derived from adipocytes that circulates in plasma, plays a central role in the regulation of energy metabolism, lipid and carbohydrate metabolism. We hypothesize that development of alcoholic fatty liver may be in part caused by ethanol inhibition of adiponectin synthesis in adipose tissue or by ethanol-induced abnormalities of adiponectin receptor- mediated signaling in the liver. The net effect of these actions of ethanol is thus to impair fatty acid disposal and to increase the rate of fatty acid synthesis, and lead to liver steatosis. Our hypothesis will be tested in both animal and cell culture models of chronic ethanol exposure. In the animal adipose tissue, we will examine the effects of ethanol feeding on mRNA and protein levels of adiponectin, and responsiveness to known inducers of adiponectin, a PPARgamma agonist, thiazolidinedione (rosiglitazone). In the animal liver, we will examine the effects of ethanol administration on levels and function of adiponectin receptors and responsiveness to the PPARgamma agonist. The effects of ethanol in adipose and liver will be correlated with lipid content, measures of total body lipid metabolism and hepatic histology. The molecular mechanisms for the effects of ethanol on adiponectin synthesis will be tested in primary adipocytes and cultured rat 3T3-L1 adipocytes. Since effects of ethanol on adiponectin and its signaling are highly regulated by dietary fatty acids, our hypothesis may provide a promising novel therapeutic strategy, which is nutritional modulation of adiponectin synthesis and adiponectin mediated signaling, for the treatment of alcoholic fatty liver disease and possibly steatohepatitis.

描述（由申请人提供）：乙醇通过对肝脂肪酸合成和氧化途径涉及的两个重要肝核转录因子的影响引起脂肪肝的发展，激活固醇调节元素结合蛋白-1（SREBP-1）的激活，以及抑制多氧化异虫体的抑制受体激活的受体（Para）。此外，乙醇对这些转录因子的影响部分是由于肝AMP激活激酶（AMPK）的乙醇抑制作用，这是一种控制肝胆固醇和甘油三甘油合成的途径的关键“代谢开关”。最近，研究确定AMPK，PPARA和SREBP-1是新发现的激素脂联素代谢作用的主要介体。脂联素是一种源自血浆中循环的脂肪细胞的激素，在能量代谢，脂质和碳水化合物代谢的调节中起着核心作用。我们假设酒精脂肪肝的发展可能部分是由脂肪组织中脂联素合成的乙醇抑制作用引起的，或者是由肝脏中脂联素受体介导的信号传导异常的乙醇诱导的异常引起的。因此，乙醇的这些作用的净作用是为了损害脂肪酸的处置并增加脂肪酸合成的速率，并导致肝脏脂肪变性。我们的假设将在慢性乙醇暴露的动物和细胞培养模型中进行检验。在动物脂肪组织中，我们将检查乙醇喂养对脂联素的mRNA和蛋白质水平的影响，以及对脂联蛋白的已知诱导剂的反应，Ppargamma激动剂，Thiazolidedione（Rosiglitazone）。在动物肝脏中，我们将检查乙醇给药对脂联素受体水平和功能的影响以及对ppargamma激动剂的反应性。乙醇在脂肪和肝脏中的影响将与脂质含量，全身脂质代谢的测量和肝组织学相关。乙醇对脂联素合成作用的分子机制将在原代脂肪细胞和培养的大鼠3T3-L1脂肪细胞中进行测试。由于乙醇对脂联素及其信号传导的影响受饮食中的脂肪酸高度调节，因此我们的假设可能提供有希望的新型治疗策略，这是脂联素合成和脂联素介导的信号传导的营养调节，用于治疗酒精脂肪肝疾病以及可能的静脉炎。