NFkB-mediated collagen regulation by SAMe in HSCs

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。酒精对肝星状细胞激活的影响与酒精诱导的氧化应激有关。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。其改善肝纤维化的作用已被证明；然而，其在肝纤维化中的分子机制尚不清楚。作为一种抗氧化剂，Same的作用涉及氧化还原敏感的转录因子核因子kB(NFkB)和调节其活性的途径(S)，它可能是介导Same抗氧化作用的关键参与者。同样，肝纤维化的缓解可能是通过调节某些转录因子来调节HSC中的胶原表达。因此，这一建议假设，抗氧化剂相同通过调节HSC中NFkB的活性来抑制酒精诱导的胶原表达。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. The effects of alcohol on the activation of HSCs have been implicated to alcohol-induced oxidative stress. 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 fibrosis is not understood. The role of SAMe as an antioxidant implicates the redox-sensitive transcription factor nuclear factor kappa B (NFkB) and the pathway(s) that regulates its activity as being a key player which may mediate the antioxidant effects of SAMe. SAMe's attenuation of liver fibrosis may occur through the regulation of certain transcription factors that modulate collagen expression in the HSC. Thus, this proposal hypothesizes that the antioxidant SAMe inhibits alcohol-induced collagen expression by modulating NFkB activity 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.