Homocysteine, Adiponectin, and Alcoholic Liver Disease

描述（由申请人提供）：慢性酒精暴露通过干扰肝脏脂肪处理导致脂肪肝的发展和维持。脂联素是一种主要由脂肪组织分泌的脂肪因子，在调节能量代谢、脂质和碳水化合物代谢中起核心作用。积累的证据表明，脂联素的下调在酒精性脂肪肝的发病过程中具有病理生理意义；然而，潜在的机制仍然难以捉摸。临床和实验研究均有长期酒精暴露导致肝脏蛋氨酸/同型半胱氨酸代谢异常和高同型半胱氨酸血症的报道，然而，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，却很少受到关注。我们的假设是，慢性酒精暴露不仅在肝脏中，而且在脂肪组织中引起蛋氨酸/同型半胱氨酸代谢异常。此外，我们假设脂肪细胞中同型半胱氨酸的积累增加，要么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，要么是来自肝脏的串扰；有助于抑制酒精性肝病（ALD）中脂联素基因的表达和分泌。在本研究中，我们将利用动物模型和细胞培养模型来评估慢性酒精喂养导致脂肪细胞中同型半胱氨酸的过度积累作为脂联素基因表达、蛋白质产生和分泌减少的机制。本项目的具体目标如下：1。进一步记录慢性饮酒对脂肪组织中蛋氨酸/同型半胱氨酸代谢的影响，并探讨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对ALD中脂联素产生的抑制作用中的因果作用；3. 阐明同型半胱氨酸调节脂联素产生的机制。营养干预的有益作用，特别是能够纠正异常的蛋氨酸/同型半胱氨酸代谢，如甜菜碱和s -腺苷蛋氨酸，已被广泛接受；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。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、抗炎症和抗纤维化的特性。慢性酒精暴露可抑制脂联素的产生，脂联素在ALD的发病机制中起重要作用。基于我们的初步发现，慢性酒精喂养导致脂肪组织中同型半胱氨酸水平升高，而同型半胱氨酸降低了原代脂肪细胞的脂联素产生，我们在这里提出肝脏和脂肪组织中蛋氨酸/同型半胱氨酸代谢的改变可能在抑制ALD中脂联素产生中起机制作用。我们将使用最先进的技术来研究这个临床相关的过程。

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.