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

SAMe 在非酒精性脂肪肝发病机制和治疗中的作用

• 批准号: 9095608
• 负责人: Shelly Chi-Loo Lu
• 金额: $ 29.72万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095608
• 关键词: Adult; Affect; Anabolism; Animal Model; Biological; Catabolism; Cells; Cessation of life; Child; Chronic; Cirrhosis; Clinic; Clinical Research; Data; Development; Educational process of instructing; Enzymes; Exhibits; Extrahepatic; Fatty Liver; Fibrosis; Funding; Genes; Goals; Grant; Growth; Health; Hepatic; High Fat Diet; Histology; Homeostasis; Human; Injury to Liver; Isoenzymes; Knock-out; Knockout Mice; Knowledge; Lead; Lecithin; Lipids; Liver; Liver diseases; Malignant - descriptor; Malignant neoplasm of liver; Mediating; Membrane; Messenger RNA; Metabolism; Methionine; Methyltransferase; Methyltransferase Gene; Modeling; Mus; Mutation; Oxidative Stress; Paper; Pathogenesis; Pathway interactions; Patients; Phosphatidylethanolamine; Phosphatidylethanolamine N-Methyltransferase; Play; Polyamines; Primary carcinoma of the liver cells; Proteins; Public Health; Publishing; Reaction; Role; S-Adenosylmethionine; Serum; Stearoyl-CoA Desaturase; Testing; Tissues; Training; Treatment Protocols; United States; Work; chronic liver disease; effective therapy; endoplasmic reticulum stress; feeding; glycine N-methyltransferase; human disease; improved; insight; knock-down; lipid metabolism; liver injury; methionine adenosyltransferase; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel marker; personalized medicine

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.

描述（由申请人提供）：-腺苷甲硫氨酸（SAMe）是主要的生物甲基供体、多胺和谷胱甘肽的前体。肝脏在 SAMe 代谢中发挥着核心作用，因为大量的 SAMe 是蛋氨酸分解代谢的产物。该反应由肝脏中的 MAT1A 编码的甲硫氨酸腺苷转移酶 (MAT) 催化。在肝脏中，SAMe 稳态由 MAT 介导的生物合成和利用控制，主要由甘氨酸 N-甲基转移酶 (GNMT) 完成。我们开发了 MAT1A 敲除 (KO) 小鼠模型，该模型表现出慢性肝 SAMe 缺陷、非酒精性脂肪性肝炎 (NASH) 和肝细胞癌 (HCC) 的发展。该模型概括了许多慢性肝病患者的情况，因为肝脏 SAMe 生物合成受损。我们还开发了 GNMT KO 小鼠模型，其中肝脏 SAMe 积累到超生理水平，小鼠出现肝损伤、NASH、纤维化以及 HCC。该模型与人类疾病相关，因为携带 GNMT 突变的儿童会出现肝损伤。这些模型有助于我们了解 SAMe 在肝脏中的各种功能。该资助目前已进入第十个年头，我们已发表 63 篇原创论文和 23 篇评论。在过去的资助期间，我们展示了 SAMe 失调如何导致肝损伤和恶性变性。我们还发现，长期高和低的肝脏 SAMe 水平会通过脂质代谢的不同改变导致 NASH，这反映在其脂质组学特征中。我们的发现使我们推测肝脏 SAMe 水平的改变是脂肪变性进展为 NASH 的重要决定因素。此外，我们假设两种 KO 模型的脂质组学分析可以帮助对 NASH 患者进行分类并个性化 NASH 治疗。提出了四个具体目标来检验这些假设： 1. 检查 SAMe 水平对个性化 NASH 治疗的影响。我们将在两个 KO 模型中测试不同的拟议 NASH 治疗方案，看看它们如何影响脂质组学和 NASH 进展。 2.检查SAMe水平对脂肪变性进展为NASH的影响。我们将测试以下假设：当通过减少 MAT1A 或 GNMT 表达来改变肝脏 SAMe 水平时，这会将简单脂肪变性的动物模型转化为 NASH。 3.检查SAMe水平对血清脂质特征的影响。我们将检查和比较 MAT1A KO 和 GNMT KO 小鼠的血清脂质组学，以生成 M 型（针对 MAT1A）和 G 型（针对 GNMT）血清脂质特征。我们将检查 467 名患者的血清脂质谱，看看他们是否可以分为这些类型。 4. 验证 NASH 患者的脂质特征。我们将前瞻性地验证一组 NASH 患者的肝脏和血清脂质特征，并将脂质谱与肝脏 SAMe 代谢物水平、MAT1A、GNMT 的表达和参与脂质代谢的基因进行比较。成功完成这些拟议目标将进一步增强我们对 SAMe 代谢改变如何影响 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。