Role of SAMe in Pathogenesis and Treatment of Non-Alcholic Fatty Liver Disease

描述(申请人提供)-腺苷蛋氨酸(同)是主要的生物甲基供体，多胺和谷胱甘肽的前体。肝脏在相同的代谢中起着核心作用，因为大部分肝脏是作为蛋氨酸分解代谢的产物产生的。该反应是由肝脏中的蛋氨酸腺苷转移酶(MAT)催化的。在肝脏中，相同的动态平衡是由MAT介导的生物合成和利用控制的，主要由甘氨酸N-甲基转移酶(GNMT)完成。我们建立了MAT1A基因敲除(KO)小鼠模型，该模型表现为慢性肝脏同型缺乏症、非酒精性脂肪性肝炎(NASH)和肝细胞癌(HCC)的发生。这个模型概括了许多慢性肝病患者的情况，因为肝脏的相同生物合成受到了损害。我们还建立了GNMT KO小鼠模型，在该模型中，肝脏中的同型半胱氨酸积聚到超生理水平，小鼠出现肝损伤、NASH、纤维化和肝细胞癌。该模型与人类疾病有关，因为携带GNMT突变的儿童有肝脏损伤。这些模型在教我们了解肝脏中相同的各种功能方面起到了重要作用。这项资助目前已进入第10个年头，我们已经发表了63篇原创论文和23篇评论。在过去的资助期间，我们展示了SIGH的失调如何导致肝脏损伤和恶性变性。我们还发现，长期高水平和低水平的肝脏通过脂代谢的不同变化导致NASH，这些变化反映在他们的脂类分布中。我们的发现使我们假设，肝脏相同水平的改变是脂肪变性进展为NASH的重要决定因素。此外，我们假设来自两个KO模型的脂类图谱有助于NASH患者的分类和个性化的NASH治疗。本文提出了四个具体目标来检验这些假设：1.检验相同水平对个性化NASH治疗的影响。我们将在两个KO模型中测试不同的NASH治疗方案，看看它们如何影响他们的脂质组学和NASH进展。2.检测同一水平对脂肪变性进展为NASH的影响。我们将检验这样一种假设，即当通过减少MAT1A或GNMT的表达来改变肝脏的相同水平时，这将使单纯性脂肪变性的动物模型转变为NASH。3.检测同一水平对血脂指标的影响。我们将检查和比较MAT1AKO和GNMT KO小鼠的血清脂质组学，以产生M型(对于MAT1A)和G型(对于GNMT)的血清脂质特征。我们将检查467名患者的血脂谱，看看他们是否可以归类为这些类型。4.验证NASH患者的血脂特征。我们将前瞻性地验证一组NASH患者的肝脏和血清脂质特征，并将其与肝脏相同代谢物水平、MAT1A、GNMT和参与脂质代谢的基因的表达进行比较。这些拟议目标的成功完成将进一步增强我们对相同代谢变化如何影响NAFLD进展的了解，并有助于个性化NASH治疗，这与公共卫生高度相关。

DESCRIPTION (provided by applicant):-Adenosylmethionine (SAMe) is the principal biological methyl donor, precursor of polyamines and GSH. Liver plays a central role in SAMe metabolism, as this is where the bulk of SAMe is generated as the product of methionine catabolism. This reaction is catalyzed by methionine adenosyltransferase (MAT), encoded by MAT1A in liver. In liver, SAMe homeostasis is controlled by MAT-mediated biosynthesis and utilization, largely accomplished by glycine N-methyltransferase (GNMT). We developed the MAT1A knockout (KO) mouse model, which exhibits chronic hepatic SAMe deficiency, development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). This model recapitulates the situation in many patients with chronic liver disease, as hepatic SAMe biosynthesis is impaired. We also developed the GNMT KO mouse model, where hepatic SAMe accumulates to supraphysiological level and the mice develop liver injury, NASH, fibrosis and also HCC. This model is relevant to human disease as children with GNMT mutations have liver injury. These models have been instrumental in teaching us about the various functions of SAMe in the liver. This grant is currently in its 10th year and we have published 63 original papers plus 23 reviews. During the past funding period we showed how dysregulation of SAMe could lead to liver injury and malignant degeneration. We also found that chronically high and low hepatic SAMe levels lead to NASH via different alterations in lipid metabolism that is reflected in their lipidomic profiles. Our finding led us to hypothesize that altered hepatic SAMe level is an important determinant in the progression of steatosis to NASH. In addition, we hypothesize that lipidomic profiling from the two KO models can help categorize NASH patients and personalize NASH treatment. Four specific aims are proposed to test these hypotheses: 1. Examine the influence of SAMe level on personalized NASH treatment. We will test different proposed NASH treatment protocols in the two KO models to see how they affect their lipidomics and NASH progression. 2. Examine the influence of SAMe level on progression from steatosis to NASH. We will test the hypothesis that when hepatic SAMe level is altered by reducing either MAT1A or GNMT expression, this will convert animal models of simple steatosis to NASH. 3. Examine the influence of SAMe level on serum lipid signature. We will examine and compare serum lipidomics in MAT1A KO to GNMT KO mice to generate M-type (for MAT1A) and G-type (for GNMT) serum lipid signatures. We will examine serum lipid profiles from 467 patients to see if they can be categorized into these types. 4. Validate lipid signatures in NASH patients. We will prospectively validate both liver and serum lipid signatures in a group of NASH patients and compare the lipid profiles to hepatic SAMe metabolite levels, expression of MAT1A, GNMT and genes involved in lipid metabolism. Successful completion of these proposed aims will further enhance our knowledge of how altered SAMe metabolism affects NAFLD progression and help personalize NASH treatment, which are highly relevant to public health.