Homocysteine, Adiponectin, and Alcoholic Liver Disease

同型半胱氨酸、脂联素和酒精性肝病

基本信息

批准号：
8516404
负责人：
ZHENYUAN SONG
金额：
$ 26.4万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-05 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516404
关键词：
Adenosylhomocysteinase Adipocytes Adipose tissue Alcohol consumption Alcoholic Fatty Liver Alcoholic Liver Diseases Alcohols Animals Attention Benign Betaine Biochemical Cell Culture Techniques Chronic Cirrhosis Clinical Research Data Development Dietary Intervention Disease Disease Progression Down-Regulation Energy Metabolism Ethanol Ethanol Metabolism Experimental Models Fatty Liver Fatty acid glycerol esters Fibrosis Gene Expression Health Hepatic Hepatocyte Homocysteine Homocystine Hyperhomocysteinemia Individual Inflammation Infusion procedures Knock-out Lead Liver Liver diseases Maintenance Mediator of activation protein Metabolism Methionine Methionine Metabolism Pathway Methyltransferase Modeling Mus Necrosis Pathogenesis Pathway interactions Physiological Plasma Play Principal Investigator Process Production Property Proteins Reaction Regulation Reporting Rodent Role S-Adenosylmethionine Staging Steatohepatitis Subarachnoid Hemorrhage Technology Therapeutic Effect United States Work adiponectin alcohol exposure base carbohydrate metabolism chronic alcohol ingestion clinically relevant design feeding inhibitor/antagonist lipid metabolism liver inflammation liver injury novel therapeutic intervention prevent programs protective effect research study restoration saturated fat transmethylation

项目摘要

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.

描述（由申请人提供）：长期接触酒精会干扰肝脏脂肪处理，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、脂质和碳水化合物代谢的调节中发挥着核心作用。积累的证据表明，脂联素产生的下调在酒精性脂肪肝疾病的过程中具有病理生理学重要性。然而，根本机制仍然难以捉摸。临床和实验研究均报道了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，然而，这种异常在脂肪组织中的发生，以及其对脂肪组织功能（特别是脂联素）调节的潜在影响表达和分泌，很少受到关注。我们的假设是，长期接触酒精不仅会导致肝脏中的蛋氨酸/同型半胱氨酸代谢异常，还会导致脂肪组织中的蛋氨酸/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，这可能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所致；有助于抑制酒精性肝病（ALD）中脂联素基因的表达和分泌。在本提案中，我们将利用动物和细胞培养模型来评估长期饮酒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。该项目的具体目标如下： 1. 进一步记录长期饮酒对脂肪组织中蛋氨酸/同型半胱氨酸代谢的影响，并探讨该过程的潜在机制； 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-腺苷甲硫氨酸，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，而且还开发新的治疗干预措施。 PHS 398/2590（修订版。09/04，重新发布 4/2006）页继续格式页公共健康相关性：酒精性肝病 (ALD) 仍然是美国的一个重要健康问题。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。长期接触酒精会导致脂联素产生受到抑制，而脂联素在 ALD 的发病机制中起着重要作用。基于我们的初步发现，即长期饮酒导致脂肪组织中同型半胱氨酸水平升高，并且同型半胱氨酸降低了初级脂肪细胞脂联素的产生，我们在此提出，肝脏和脂肪组织中蛋氨酸/同型半胱氨酸代谢的改变可能发挥机制作用抑制 ALD 中脂联素的产生。我们将使用最先进的技术来研究这一临床相关过程。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extracellular signal-regulated kinases 1/2 suppression aggravates transforming growth factor-beta1 hepatotoxicity: a potential mechanism for liver injury in methionine-choline deficient-diet-fed mice.

细胞外信号调节激酶 1/2 抑制加重转化生长因子-β1 肝毒性：蛋氨酸胆碱缺乏饮食喂养小鼠肝损伤的潜在机制。

DOI：
发表时间：
2010-11
期刊：
影响因子：
0
作者：
Wang, Zhigang;Yao, Tong;Song, Zhenyuan
通讯作者：
Song, Zhenyuan

Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease.

纠正受损的脂肪组织甲基化状态和脂肪分解反应有助于甜菜碱在酒精性肝病小鼠模型中的保肝作用。

DOI：
发表时间：
2014-09
期刊：
影响因子：
7.3
作者：
Dou, Xiaobing;Xia, Yongliang;Chen, Jing;Qian, Ying;Li, Songtao;Zhang, Ximei;Song, Zhenyuan
通讯作者：
Song, Zhenyuan

Protection of nicotinic acid against oxidative stress-induced cell death in hepatocytes contributes to its beneficial effect on alcohol-induced liver injury in mice.

烟酸保护肝细胞免受氧化应激诱导的细胞死亡，有助于其对小鼠酒精性肝损伤的有益作用。

DOI：
10.1016/j.jnutbio.2012.12.012
发表时间：
2013-08
期刊：
The Journal of nutritional biochemistry
影响因子：
0
作者：
Dou X;Shen C;Wang Z;Li S;Zhang X;Song Z
通讯作者：
Song Z

4-Hydroxynonenal differentially regulates adiponectin gene expression and secretion via activating PPARγ and accelerating ubiquitin-proteasome degradation.

4-Hydroxynonenal 通过激活 PPARγ 和加速泛素蛋白酶体降解来差异调节脂联素基因表达和分泌。

DOI：
发表时间：
2012-02-26
期刊：
影响因子：
4.1
作者：
Wang, Zhigang;Dou, Xiaobing;Gu, Dongfang;Shen, Chen;Yao, Tong;Nguyen, Van;Braunschweig, Carol;Song, Zhenyuan
通讯作者：
Song, Zhenyuan

Glutathione disulfide sensitizes hepatocytes to TNFα-mediated cytotoxicity via IKK-β S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease.

谷胱甘肽二硫化物通过 IKK-β S-谷胱甘肽使肝细胞对 TNFα 介导的细胞毒性敏感：非酒精性脂肪肝的潜在机制。