NFkB-mediated collagen regulation by SAMe in HSCs

描述（由申请人提供）：肝纤维化的特征是I型胶原沉积增加，改变肝脏的正常结构，导致肝功能障碍。许多病因都与肝纤维化有关，在美国，慢性饮酒是肝纤维化的主要原因。肝星状细胞（HSC）是肝脏中主要的细胞类型，在纤维化过程中负责过多的胶原合成。暴露于酒精后，HSC从一个静止的、储存维生素a的细胞转变为一个活化的、产生胶原的肌成纤维细胞样细胞。酒精对hsc活化的影响与酒精诱导的氧化应激有关。乙醇的代谢导致自由基的产生，而自由基与酒精引起的肝损伤有关。因此，通过使用抗氧化剂减少氧化损伤可以作为包括酒精在内的多种药物引起的肝脏疾病的成功治疗方法。s -腺苷- i - l -蛋氨酸（SAMe）是谷胱甘肽的前体，具有潜在的抗氧化剂作用。SAMe已被证明可改善肝纤维化；然而，SAMe在肝纤维化中的分子机制尚不清楚。SAMe作为抗氧化剂的作用涉及氧化还原敏感转录因子核因子κ B （NFkB）和调节其活性的途径，作为可能介导SAMe抗氧化作用的关键参与者。SAMe对肝纤维化的减弱可能是通过调节HSC中胶原表达的某些转录因子来实现的。因此，本研究假设抗氧化剂SAMe通过调节HSC中NFkB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新的治疗方法，旨在防止氧化性肝纤维化的进展。

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.