Molecular mechanisms of SAMe in hepatic stellate cells

描述(申请人提供)：肝纤维化的特征是I型胶原沉积增加，它改变了肝脏的正常结构，导致肝功能障碍。许多病因都与肝纤维化有关，在美国，长期饮酒是导致肝纤维化的主要原因。肝星状细胞(HSC)是肝脏中的主要细胞类型，在纤维化过程中负责过度合成胶原。酒精暴露后，HSC经历了从静止的、储存维生素A的细胞到激活的、产生胶原的肌成纤维细胞样细胞的转变。除了酒精对HSC的影响外，酒精还会诱导氧化应激，氧化应激在酒精性肝病中起着关键作用。乙醇的新陈代谢导致自由基的产生，而自由基的产生与酒精性肝损伤的发展有关。因此，通过使用抗氧化剂来减少氧化损伤可能是治疗包括酒精在内的多种因素引起的肝病的成功治疗方法。谷胱甘肽的前体S-腺苷-L-蛋氨酸(SAME)具有潜在的抗氧化剂作用。同样的作用已被证明可以改善肝纤维化；然而，其在肝病中的分子机制还不是很清楚。作为一种抗氧化剂，Same的作用意味着氧化还原敏感的转录因子，如核因子kB(NFkB)和激活蛋白-1(AP-1)是关键角色，可能介导Same的抗氧化作用，保护肝脏免受氧化损伤。此外，由于氧化应激可导致炎症，因此其对肿瘤坏死因子-α和其他细胞因子(如IL-6和IL-10)基因表达的影响将是重要的，特别是考虑到这些细胞因子也调节胶原的表达。因此，本研究旨在探讨抗氧化剂SAME对HSC中NFkB和AP-1的激活以及对TNF-α、IL-6和IL-10表达的影响的分子机制。这些研究的结果将有助于开发旨在防止氧化诱导的肝纤维化进展的新疗法。

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.