S-adenosylmethionine treatment in alcoholic cirrhosis

项目摘要 酒精性肝硬变是美国发病率和死亡率的主要原因。ITS中的关键驱动因素之一 发病机制是肝脏蛋氨酸腺苷转移酶1A(MAT1A)表达减少，导致 降低肝脏S-腺苷蛋氨酸(同)水平。同一水平的降低导致了几个 不利的细胞内后果，包括促进免疫细胞的炎性级联，如 作为巨噬细胞通过脂多糖(LPS)、氧化应激和内质网(ER)应激。那里 是广泛的临床前证据，支持将其用于酒精性肝病，但人体试验使用 同样在酒精性肝硬变中也没有提供明确的疗效证据。在西班牙进行的一次大型试验 其中一名研究人员(何塞·马托博士)显示了同样的治疗方法(分两年服用1200毫克)。 降低了不太严重的酒精性肝硬化症的死亡率，但这是作为一项事后分析完成的，没有 并对其作用机理进行了探讨。在美国进行的一项较短时间(六个月)的试验是阴性的，但辍学率 是非常高的，禁欲被要求留在试验中，这可能掩盖了同样的效果 因为安慰剂组有明显的改善，可能是由于禁欲。此应用程序涉及两个 美国的学术中心(洛杉矶的锡达斯-西奈医学中心和印第安纳大学 医院)、西班牙一家研究机构(CIC BioGUNE)和NIAAA内壁肝脏研究科学家(Bin博士 Gao)在患有酒精性肝硬变的人类身上进行了同样的检测。我们提出了一种随机双盲安慰剂 酒精性肝硬变患者应用SAME的疗效及其机制的对照研究 在现实世界中，通过鼓励但不要求禁欲来实现。此外，我们还计划调查 相同的潜在机制(S)，并使用新的代谢组学跟踪治疗反应和检查 基线代谢组学特征与对相同药物的反应相关。提出了两个具体目标：目标1：我们 将进行一项随机双盲安慰剂对照研究，在相同的(1,200毫克/天)之间进行 酒精性肝硬变患者(ChildA级和B级)和安慰剂治疗24个月。这个 主要终点将是组间任何原因的死亡率。关键的次要端点是 肠道通透性、血清内毒素、免疫细胞激活标志物和肝脏特异性的变化 死亡率。液质联用与核磁共振互补代谢组学研究 基线的波谱和试验结束时的核磁共振将评估治疗的反应以及是否某些 简档预测对相同的反应。目标2：我们将确定相同处理对氧化应激的影响， 内质网应激诱导线粒体DNA和细胞色素P4502E1富含微粒。我们的应用程序 是新颖的，与没有得到证实的有效治疗方法的未得到满足的需求研究领域相关。 此外，我们的建议可能会为酒精性肝硬变和酒精性肝硬变的作用提供新的机制见解。 代谢组学在这些患者个体化治疗中的应用。

Project Summary Alcoholic cirrhosis is a leading cause of morbidity and mortality in the US. One of the key drivers in its pathogenesis is the reduction in hepatic methionine adenosyltransferase 1A (MAT1A) expression resulting in the reduction in hepatic S-adenosylmethionine (SAMe) levels. The reduction in SAMe level leads to several adverse intracellular consequences, which include promoting the inflammatory cascades in immune cells such as macrophages by lipopolysaccharides (LPS), oxidative stress and endoplasmic reticulum (ER) stress. There is extensive preclinical evidence that support the use of SAMe in alcoholic liver disease but human trials using SAMe in alcoholic cirrhosis have not provided clear evidence of efficacy. One large trial conducted in Spain by one of the co-investigators (Dr. José Mato) showed SAMe treatment (1200 mg in divided doses for two years) reduced the mortality of less advanced alcoholic cirrhotics but this was done as a post-hoc analysis and no mechanism was investigated. A shorter (six months) trial done in the U.S. was negative but the dropout rate was very high and abstinence was required to stay in the trial, which may have obscured the SAMe effect since placebo group had marked improvement likely due to abstinence. This application involves two academic centers in the United States (Cedars-Sinai Medical Center in Los Angeles and Indiana University Hospital), a research institute in Spain (CIC bioGUNE), and NIAAA intramural liver research scientist (Dr. Bin Gao) to examine SAMe in humans with alcoholic cirrhosis. We propose a randomized double-blind placebo controlled trial to determine the efficacy of SAMe and its mechanistic effects in patients with alcoholic cirrhosis in the real world setting by encouraging but not requiring abstinence. In addition, we aim to investigate the underlying mechanism(s) of SAMe and use novel metabolomics to follow response to treatment and examine if baseline metabolomics profiles correlate with response to SAMe. Two specific aims are proposed: Aim 1: we will perform a randomized double-blind placebo controlled study between SAMe (1,200 mg/day given in two divided dose) and placebo, in patients with alcoholic cirrhosis (Child class A and B) for 24 months. The primary endpoint will be the mortality of any causes between groups. The key secondary endpoints are the changes in intestinal permeability, serum endotoxin, markers of immune cell activations, and liver-specific mortality. Complementary metabolomics using liquid-chromatography-mass spectrometry (LC-MS) and NMR spectroscopy at baseline and NMR at the end of the trial will assess response to treatment and whether certain profiles predict response to SAMe. Aim 2: we will determine the effect of SAMe treatment on oxidative stress, and ER-stress induced mitochondrial DNA and cytochrome P450 2E1 enriched microparticles. Our application is novel and relevant to an un-met need area of research where no proven effective treatments are available. In addition, our proposal may unveil novel mechanistic insights on the effect of SAMe in alcoholic cirrhosis and the use of metabolomics in personalized treatment of these patients.