ALTERED METHIONINE METABOLISM IN ALCOHOLIC LIVER INJURY

酒精性肝损伤中蛋氨酸代谢的改变

• 批准号: 6922927
• 负责人: Shelly Chi-Loo Lu
• 金额: $ 37.19万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922927
• 关键词: Kupffer' s cell; S adenosylmethionine; alcoholic liver cirrhosis; aminoacid metabolism; cell proliferation; collagen; disease /disorder model; endotoxins; enzyme activity; ethanol; homocysteine; laboratory rat; liver disorder chemotherapy; methionine; methionine adenosyltransferase; nonhuman therapy evaluation; oxidative stress; pathologic process; protein biosynthesis; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha

DESCRIPTION: (Adapted from the Applicant's Abstract): Altered hepatic methionine metabolism and hyperhomocysteinemia are well recognized in alcoholic liver disease but the exact mechanisms and pathogenetic consequences are not well defined. The protective mechanisms of SAM in alcoholic liver injury also remain ill defined. We hypothesize that abnormal hepatic methionine metabolism has important pathogenetic consequences in the development of alcoholic liver injury. This hypothesis is based on several novel key findings. First, using the Tsukamoto-French intragastric ethanol-feeding model, we observed a switch in the expression of methionine adenosyltransferase (MAT), the key enzyme that catabolizes methionine to form S-adenosyl-methionine (SAM) in both whole liver and Kupffer cells. In the liver, this was associated with decreased SAM level and global DNA hypomethylation. Second, homocysteine in pathologically relevant concentrations induced the expression of tissue inhibitor of metalloproteinases-4 (TIMP- 1) and a 1(I) procollagen in a hepatic stellate cell line and collagen production in primary cultures of hepatic stellate cells. The current proposal will extend these findings, test several hypotheses and examine the protective mechanisms of SAM. The aims are: 1) examine changes in hepatic methionine metabolism during the development of ethanol-induced liver injury and the effect of SAM treatment - using the intragastric ethanol and high fat feeding, define stage-specific changes in methionine metabolism, examine key enzymes that affect the steady state SAM and homocysteine levels, investigate consequence of these changes and the effect of SAM treatment; 2) define the role of homocysteine in ethanol-induced liver fibrosis -evaluate the effect of homocysteine on markers of fibrogenesis in primary cultures of stellate cells and examine biological markers such as collagen production and proliferation, test the hypothesis that there is increased homocysteine release from hepatocytes of ethanol-fed animals due to abnormalities in methionine metabolism, which can exert paracrine effects on stellate cells to induce fibrogenesis; 3) examine changes in MAT expression and SAM homeostasis in Kupffer cells during the course of ethanol-induced liver injury and the effect of SAM treatment - test the hypothesis that the switch in MAT expression in Kupffer cells may result in lower SAM level and induce TNF expression, examine the effect of SAM treatment on TNF expression in vitro in LPS-stimulated normal Kupffer cells, ex-vivo in Kupffer cells obtained from ethanol-fed animals, and in vivo, investigate the mechanisms of SAM's suppressive effect on TNF expression.

描述：（改编自申请人的摘要）：肝的更改 蛋氨酸代谢和高脑结晶质血症在酒精中得到广泛认可 肝病，但确切的机制和致病后果不是 定义很好。酒精肝损伤中SAM的保护机制 保持不明的定义。我们假设肝蛋氨酸代谢异常 在酒精性肝脏的发展中具有重要的致病后果 受伤。该假设基于几个新的关键发现。首先，使用 tsukamoto-french胃内乙醇喂养模型，我们观察到开关 在蛋氨酸腺基转移酶（MAT）的表达中， 在整个肝脏中分解蛋氨酸以形成S-腺苷甲硫代氨酸（SAM） 和Kupffer细胞。在肝脏中，这与SAM水平降低有关 和全局DNA降压甲基化。其次，在病理上相关的同型半胱氨酸 浓度诱导的组织抑制剂的表达 金属蛋白酶-4（TIMP-1）和肝星状的1（i）胶原蛋白 细胞系和胶原蛋白产生肝星状的原发性培养物 细胞。当前的建议将扩展这些发现，检验几个假设 并检查SAM的保护机制。目的是：1）检查更改 在乙醇诱导的肝蛋氨酸代谢中 肝损伤和SAM治疗的作用 - 使用胃内乙醇 和高脂肪进食，定义蛋氨酸代谢的特定阶段特异性变化， 检查影响稳态SAM和同型半胱氨酸水平的关键酶， 研究这些变化的后果和SAM治疗的影响； 2） 定义同型半胱氨酸在乙醇诱导的肝纤维化中的作用 - 评估 同型半胱氨酸对主要培养物纤维化标记的影响 星状细胞并检查生物标记物，例如胶原蛋白产生和 增殖，检验释放同型半胱氨酸增加的假设 由于蛋氨酸异常而引起的乙醇喂养动物的肝细胞 代谢，可以对星状细胞发挥旁分泌作用以诱导 纤维化； 3）检查MAT表达和SAM稳态的变化 在乙醇引起的肝损伤过程中，库普弗细胞和效果 SAM处理 - 检验MAT表达开关中的假设 Kupffer细胞可能导致SAM水平较低并诱导TNF表达，检查 SAM处理对LPS刺激的正常体外TNF表达的影响 Kupffer细胞，从乙醇喂的动物获得的库普弗细胞中的前体细胞， 在体内，研究SAM对TNF的抑制作用的机制 表达。

项目成果

Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury.

• DOI: 10.1093/ajcn/76/5.1177s
• 发表时间: 2002-11
• 期刊: The American journal of clinical nutrition
• 作者: M. Martínez‐Chantar;E. R. García-Trevijano;U. Latasa;Isabel Pérez-Mato;Manuel M Sánchez del Pino;F. Corrales;M. Ávila;J. Mato

Molecular profiling of hepatocellular carcinoma in mice with a chronic deficiency of hepatic s-adenosylmethionine: relevance in human liver diseases.

• DOI: 10.1021/pr050429v
• 发表时间: 2006-03
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: E. Santamaría;J. Muñoz;J. Fernández-Irigoyen;L. Sesma;M. I. Mora;C. Berasain;Shelly C. Lu;J. Mato;J. Prieto;M. Ávila;F. Corrales