Regulation of methionine metabolism in NASH by PPARgamma

PPARgamma 对 NASH 中蛋氨酸代谢的调节

• 批准号: 10449646
• 负责人: Jose Cordoba-Chacon
• 金额: $ 11.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449646
• 关键词: Address; Adult; Affect; Agonist; Anti-Inflammatory Agents; Back; Betaine; Cells; ChIP-seq; Cholesterol; Clinical Trials; Critical Pathways; Data; Development; Diabetes Mellitus; Diet; Disease; Extrahepatic; FDA approved; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Fructose; Future; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Gene Expression Regulation; Genes; Health; Hepatic; Hepatocyte; Homocysteine; Impairment; Inflammation; Injury; Insulin; Knock-out; Lecithin; Ligands; Lipids; Liver; Manuscripts; Measures; Mediating; Mentored Research Scientist Development Award; Metabolism; Methionine; Methionine Metabolism Pathway; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonpharmacologic Therapy; Nuclear Receptors; Obese Mice; Outcome; PPAR gamma; Pathogenesis; Patients; Pharmacological Treatment; Pharmacology; Phosphatidylethanolamine; Phosphatidylethanolamine N-Methyltransferase; Play; Population; Pre-Clinical Model; Prevalence; Process; Production; Publishing; Regulation; Reporting; Role; S-Adenosylhomocysteine; Sampling; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Tissue Therapy; Very low density lipoprotein; Work; betaine-homocysteine methyltransferase; chronic liver disease; clinical practice; diet-induced obesity; fatty liver disease; feeding; improved; innovation; insulin sensitivity; insulin sensitizing drugs; lipid biosynthesis; liver injury; metabolomics; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel strategies; novel therapeutics; prevent; stable isotope; success; transcriptome sequencing; transmethylation; uptake

Project Summary/Abstract Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease with a worldwide prevalence of 25%, and without a FDA-approved pharmacological therapy. Thiazolidinediones (TZD) are the agonists of peroxisome proliferator-activated receptor γ (PPARγ), and they are a potential therapy for NAFLD. However, PPARγ is a nuclear receptor and well-known steatogenic factor expressed in hepatocytes that contributes to the development of NAFLD by enhancing hepatic de novo lipogenesis (DNL) and fatty acid uptake. We have assessed the role of hepatocyte PPARγ in the development of non-alcoholic steatohepatitis (NASH) with adult-onset hepatocyte-specific Pparg knockout (Pparg∆Hep) mice in our K01 award. Specifically, we have shown that hepatocyte PPARγ contributes to the onset of inflammation and fibrosis in mice with NASH, suggesting a deleterious role of hepatocyte PPARγ on liver health. In addition, loss of hepatocyte PPARγ in Pparg∆Hep mice enhances the anti-steatogenic, anti-inflammatory, and anti-fibrogenic actions of TZD in a model of NASH. Interestingly, our RNAseq and metabolomics data indicated that hepatocyte PPARγ altered the metabolism of methionine in the liver. Methionine plays a key protective role against NAFLD, and the effect of PPARγ on its metabolism may explain why TZD-mediated activation of hepatocyte PPARγ reduced the therapeutic effects of TZD in NASH. In this project, we hypothesize that hepatocyte PPARγ disrupts methionine metabolism and promotes steatosis and liver injury by regulating gene expression and the ability to methylate phosphatidylethanolamine and homocysteine. In order to test this hypothesis, we will identify the genes regulated by PPARγ to control the use of methionine in NASH with chromatin immunoprecipitation sequencing in samples of control and Pparg∆Hep mice treated with TZD (Aim 1). In addition, we will determine if PPARγ directly disrupts the use of methionine in mouse primary hepatocytes of control and Pparg∆Hep mice with NASH using stable isotopes (Aim 2). Overall, we will determine how hepatocyte PPARγ regulates directly methionine metabolism in pathophysiological conditions. The results of this project will help us to develop novel approaches in our R01 proposals that will target specific mechanisms in preclinical models to improve NASH reversion.

项目摘要/摘要 非酒精性脂肪肝病（NAFLD）是慢性肝病的主要原因 患病率为25％，没有FDA批准的药物治疗。噻唑烷二酮（TZD）是 过氧化素增殖物激活受体γ（PPARγ）的激动剂，它们是NAFLD的潜在疗法。 但是，PPARγ是一种核接收器，是肝细胞中表达的众所周知的脂肪生成因子， 通过增强从头脂肪生成（DNL）和脂肪酸摄取来促进NAFLD的发展。 我们已经评估了肝细胞PPARγ在非酒精性脂肪性肝炎（NASH）发展中的作用 在我们的K01奖中，成人发作的肝细胞特异性PPARG敲除（PPARGΔHEP）小鼠。具体来说，我们有 表明肝细胞PPARγ有助于纳什的小鼠炎症和纤维化的发作 表明肝细胞PPARγ在肝脏健康中发挥了有害作用。此外，肝细胞PPARγ在 PPARGΔHEP小鼠在模型中增强了TZD的抗杀菌性，抗炎症和抗纤维化作用 纳什。有趣的是，我们的RNASEQ和代谢组学数据表明，肝细胞PPARγ改变了 甲二氨酸的代谢。蛋氨酸对NAFLD起着关键的保护作用，以及 PPARγ关于其代谢可能会解释为什么TZD介导的肝细胞PPARγ激活降低了 TZD在NASH中的治疗作用。在这个项目中，我们假设肝细胞PPARγ破坏了甲酯 代谢并通过控制基因表达和甲基化能力来促进脂肪变性和肝损伤 磷脂酰乙醇胺和同型半胱氨酸。为了检验这一假设，我们将确定受调节的基因 通过PPARγ来控制样品中的染色质免疫沉淀在NASH中的使用 用TZD处理的对照和PPARGΔHEP小鼠（AIM 1）。另外，我们将确定PPARγ是否直接破坏 使用稳定 同位素（AIM 2）。总体而言，我们将确定肝细胞PPARγ如何直接调节蛋氨酸代谢 病理生理状况。该项目的结果将帮助我们在R01中开发新颖的方法 将针对临床前模型中特定机制以改善NASH反向的建议。