Homocysteine, Adiponectin, and Alcoholic Liver Disease

描述(申请人提供)：长期接触酒精会干扰肝脏脂肪的处理，从而导致脂肪肝的发生和维持。脂联素是一种主要由脂肪组织分泌的脂肪因子，在能量代谢、脂肪代谢和碳水化合物代谢中起着重要的调节作用。越来越多的证据表明，脂联素的生成下调在酒精性脂肪性肝病的发病过程中具有重要的病理生理意义；然而，其潜在的机制仍不清楚。长期酒精暴露引起的肝脏蛋氨酸/同型半胱氨酸代谢异常和高同型半胱氨酸血症已在临床和实验研究中得到报道，但这种异常在脂肪组织中的发生及其在脂肪组织功能调节中的潜在意义，特别是脂联素的表达和分泌，却鲜有人关注。我们的假设是，长期酒精暴露不仅会在肝脏中诱导蛋氨酸/同型半胱氨酸代谢异常，而且在脂肪组织中也会引起异常。此外，我们假设，无论是通过酒精诱导的蛋氨酸/同型半胱氨酸代谢的内源性改变或来自肝脏的串扰，增加脂肪细胞中同型半胱氨酸的积累，都有助于抑制酒精性肝病(ALD)中脂联素基因的表达和分泌。在这项建议中，我们将利用动物和细胞培养模型来评估长期酒精喂养导致脂肪细胞中同型半胱氨酸过度积累，作为脂联素基因表达、蛋白质合成和分泌减少的机制。本项目的具体目标如下：1.进一步记录长期饮酒对脂肪组织蛋氨酸/同型半胱氨酸代谢的影响，并探索参与这一过程的潜在机制；2.确定脂肪细胞中同型半胱氨酸积累增加对脂联素产生的影响及其在慢性酒精暴露抑制ALD脂联素产生中的因果作用；3.阐明同型半胱氨酸调节脂联素产生的机制。营养干预的有益效果，特别是那些能够纠正蛋氨酸/同型半胱氨酸代谢异常的效果，如甜菜碱和S-腺苷蛋氨酸，已经被广泛接受；因此，我们的方法不仅旨在更全面地了解ALD的机制，而且还旨在开发新的治疗干预措施。PHS 398/2590(版本09/04,2006年4月重新发布)页面延续格式页面公共卫生相关性：酒精性肝病(ALD)在美国仍然是一个重要的健康问题。脂联素是一种主要由脂肪组织分泌的可溶性介质，具有抗脂肪变性、抗炎和抗纤维化的特性。慢性酒精暴露可抑制脂联素的生成，在酒精性肝病的发病机制中起重要作用。根据我们的初步发现，长期饮酒导致脂肪组织同型半胱氨酸水平升高，同型半胱氨酸减少原代脂肪细胞产生脂联素，我们认为肝脏和脂肪组织蛋氨酸/同型半胱氨酸代谢的改变可能在ALD抑制脂联素产生中起作用。我们将使用最先进的技术来研究这一临床相关过程。

DESCRIPTION (provided by applicant): Chronic alcohol exposure causes the development and maintenance of fatty liver by interfering hepatic fat disposal. Adiponectin, an adipokine predominantly secreted by adipose tissue, plays a central role in the regulation of energy metabolism, lipid and carbohydrate metabolism. Accumulated evidence suggests that down- regulation of adiponectin production has patho-physiological importance in the process of alcoholic fatty liver disease; however, the underlying mechanisms are still elusive. Abnormal hepatic methionine/homocysteine metabolism and hyperhomocysteinemia induced by prolonged alcohol exposure has been reported both in clinical and experimental studies, however, the occurrence of this abnormality in adipose tissue, as well as its potential implication in the regulation of adipose tissue function, specifically adiponectin expression and secretion, has received very few attention. It is our hypothesis that chronic alcohol exposure induces abnormal methionine/homocysteine metabolism not only in the liver, but also in the adipose tissue. Furthermore, we hypothesize that increased accumulation of homocysteine in the adipocytes, either via alcohol-induced endogenous alteration in methionine/homocysteine metabolism or a cross-talk from the liver; contribute to the suppression of adiponectin gene expression and secretion in alcoholic liver disease (ALD). In this proposal, we will utilize both animal and cell culture models to evaluate excessive accumulation of homocysteine in the adipocytes by chronic alcohol feeding as a mechanism for decreased adiponectin gene expression, protein production and secretion. The specific objectives of this project are as follows: 1. Further document the effects of chronic alcohol consumption on methionine/homocysteine metabolism in adipose tissues and explore potential mechanisms involved in this process; 2. Determine the effects of increased homocysteine accumulation in adipocytes on adiponectin production and its causal role in the inhibitory effects of chronic alcohol exposure on adiponectin production in ALD; 3. Elucidate mechanisms whereby homocysteine modulates adiponectin production. The beneficial effects of nutritional intervention, specifically these being able to rectify abnormal methionine/homocysteine metabolism such as betaine and S-adenosylmethionine, have been well-accepted; thus, our approach is designed to not only more completely understand the mechanisms of ALD, but also to develop new therapeutic interventions. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Alcoholic liver disease (ALD) remains an important health problem in the United States. Adiponectin is a soluble mediator predominantly secreted by adipose tissue and in possession of properties of anti-steatosis, anti-inflammation, and anti-fibrosis. Chronic alcohol exposure results in suppressed adiponectin production, which plays an important role in the pathogenesis of ALD. Based on our preliminary findings that chronic alcohol feeding caused elevation of homocysteine levels in the adipose tissue and homocysteine decreased adiponectin production by primary adipocytes, we propose here that altered methionine/homocysteine metabolism both in the liver and in the adipose tissue may play a mechanistic role in the suppression of adiponectin production in ALD. We will use the state-of-the-art technologies to investigate this clinically relevant process.