Molecular mechanisms of SAMe in hepatic stellate cells

SAMe在肝星状细胞中的分子机制

• 批准号: 6593558
• 负责人: LAURA W SCHRUM
• 金额: $ 6.5万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6593558
• 关键词: JUN kinase; S adenosylmethionine; acetaldehyde; collagen; enzyme activity; enzyme linked immunosorbent assay; ethanol; gene expression; interleukin 10; interleukin 6; laboratory rat; liver cells; nuclear factor kappa beta; phosphorylation; tissue /cell culture; transcription factor; transfection; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Hepatic fibrosis is characterized by an increase in type I collagen deposition which alters the normal architecture of the liver leading to liver dysfunction. Many etiologies have been associated with hepatic fibrosis with chronic alcohol consumption being the leading cause of liver fibrosis in the United States. The hepatic stellate cell (HSC) is the primary cell type in the liver responsible for excess synthesis of collagen during fibrosis. Following exposure to alcohol, the HSC undergoes a transformation from a quiescent, vitamin A storing cell to that of an activated, collagen producing myofibroblast-like cell. In addition to the effects of alcohol on the HSC, alcohol also induces oxidative stress which plays a key role in alcoholic liver disease. The metabolism of ethanol leads to the production of free radicals that have been linked to the development of alcohol-induced liver injury. Thus, diminishing oxidative damage by the use of antioxidants may serve as successful therapeutic treatments for liver diseases caused by numerous agents including alcohol. S-adenosyI-L-methionine (SAMe), the precursor of glutathione, has potential usefulness as an antioxidant. SAMe has been shown to improve hepatic fibrosis; however, the molecular mechanisms of SAMe in liver disease is not well understood. The role of SAMe as an antioxidant implicates redox-sensitive transcription factors such as nuclear factor kappa B (NFkB) and activator protein-1 (AP-1) as being key players which may mediate the antioxidative effects of SAMe and protect the liver against oxidative damage. Additionally, since oxidative stress can lead to inflammation, the effects of SAMe on TNF-alpha and other cytokines (such as IL-6 and IL-10) gene expression would be important, especially considering that these cytokines also modulate collagen expression. Thus, this proposal is aimed at investigating the molecular mechanisms of the antioxidant SAMe on activation of NFkB and AP-1, and expression of TNF-alpha, IL-6 and IL-10 in the HSC. The results of these studies will aid in the development of novel therapeutics aimed at preventing the progression of oxidative-induced hepatic fibrosis.

描述（由申请人提供）：肝纤维化的特征是 I 型胶原沉积增加，这改变了肝脏的正常结构，导致肝功能障碍。许多病因与肝纤维化有关，在美国，长期饮酒是肝纤维化的主要原因。肝星状细胞（HSC）是肝脏中负责纤维化过程中胶原蛋白过度合成的主要细胞类型。接触酒精后，HSC 会从静止的维生素 A 储存细胞转变为活化的、产生胶原蛋白的肌成纤维细胞样细胞。除了酒精对 HSC 的影响外，酒精还会诱发氧化应激，这在酒精性肝病中起着关键作用。乙醇的代谢会导致自由基的产生，自由基与酒精引起的肝损伤的发生有关。因此，通过使用抗氧化剂减少氧化损伤可以成功治疗由包括酒精在内的多种物质引起的肝脏疾病。 S-腺苷-L-甲硫氨酸 (SAMe) 是谷胱甘肽的前体，具有作为抗氧化剂的潜在用途。 SAMe 已被证明可以改善肝纤维化；然而，SAMe 在肝病中的分子机制尚不清楚。 SAMe 作为抗氧化剂的作用表明，氧化还原敏感的转录因子，如核因子 kappa B (NFkB) 和激活蛋白 1 (AP-1) 是可能介导 SAMe 的抗氧化作用并保护肝脏免受氧化损伤的关键参与者。 此外，由于氧化应激可导致炎症，SAMe 对 TNF-α 和其他细胞因子（如 IL-6 和 IL-10）基因表达的影响非常重要，特别是考虑到这些细胞因子也调节胶原蛋白表达。因此，本提案旨在研究抗氧化剂SAMe对HSC中NFkB和AP-1的激活以及TNF-α、IL-6和IL-10的表达的分子机制。这些研究的结果将有助于开发旨在预防氧化诱导的肝纤维化进展的新疗法。