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: 9275319
• 负责人: Shelly Chi-Loo Lu
• 金额: $ 29.56万
• 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/9275319
• 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; Hepatic; High Fat Diet; Histology; Homeostasis; Human; Impairment; 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; Pharmacology; 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; 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; prospective; public health relevance

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.

性状（由申请人提供）：腺苷甲硫氨酸（SAMe）是主要的生物甲基供体，是多胺和GSH的前体。肝脏在SAMe代谢中起着核心作用，因为这是大部分SAMe作为蛋氨酸催化剂的产物产生的地方。该反应由肝脏中由MAT 1A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MAT 1A基因敲除（KO）小鼠模型，该模型表现出慢性肝脏SAMe缺乏，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SAMe积累到超生理水平，并且小鼠发生肝损伤、NASH、纤维化以及HCC。该模型与人类疾病相关，因为具有GNMT突变的儿童具有肝损伤。这些模型有助于我们了解SAMe在肝脏中的各种功能。该补助金目前已进入第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SAMe的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水平通过脂质代谢的不同改变导致NASH，这反映在它们的脂质组学特征中。我们的发现使我们假设改变的肝脏SAMe水平是脂肪变性进展为NASH的重要决定因素。此外，我们假设来自两种KO模型的脂质组学分析可以帮助对NASH患者进行分类和个性化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。我们将在两种KO模型中测试不同的NASH治疗方案，以了解它们如何影响脂质组学和NASH进展。2.检查SAMe水平对从脂肪变性进展为NASH的影响。我们将检验以下假设：当通过降低MAT 1A或GNMT表达来改变肝脏SAMe水平时，这将使单纯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。我们将检查并比较MAT 1A KO与GNMT KO小鼠的血清脂质组学，以生成M型（对于MAT 1A）和G型（对于GNMT）血清脂质特征。我们将检查467例患者的血脂谱，看看他们是否可以分为这些类型。4. NASH患者的血脂特征。我们将前瞻性验证一组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、MAT 1A、GNMT和脂质代谢相关基因的表达进行比较。成功完成这些目标将进一步提高我们对SAMe代谢改变如何影响NAFLD进展的认识，并有助于个性化NASH治疗，这与公共卫生高度相关。