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.

项目概要/摘要 非酒精性脂肪性肝病（NAFLD）是全球范围内慢性肝病的主要原因 患病率为 25%，且未经 FDA 批准的药物治疗。噻唑烷二酮类 (TZD) 是 过氧化物酶体增殖物激活受体 γ (PPARγ) 的激动剂，它们是 NAFLD 的潜在治疗方法。 然而，PPARγ 是一种核受体，也是众所周知的肝细胞表达的脂肪形成因子， 通过增强肝脏脂肪生成 (DNL) 和脂肪酸摄取，促进 NAFLD 的发展。 我们评估了肝细胞 PPARγ 在非酒精性脂肪性肝炎 (NASH) 发展中的作用 成年发病的肝细胞特异性 Pparg 敲除 (PpargΔHep) 小鼠获得了我们的 K01 奖。具体来说，我们有 研究表明，肝细胞 PPARγ 会导致 NASH 小鼠炎症和纤维化的发生， 表明肝细胞 PPARγ 对肝脏健康具有有害作用。此外，肝细胞PPARγ的丢失 PpargΔHep 小鼠在模型中增强 TZD 的抗脂肪形成、抗炎和抗纤维形成作用 NASH 的。有趣的是，我们的 RNAseq 和代谢组学数据表明肝细胞 PPARγ 改变了 蛋氨酸在肝脏中的代谢。蛋氨酸对 NAFLD 具有重要的保护作用， PPARγ 对其代谢的影响可能解释了为什么 TZD 介导的肝细胞 PPARγ 激活会降低 TZD 对 NASH 的治疗作用。在这个项目中，我们假设肝细胞 PPARγ 会破坏蛋氨酸 通过调节基因表达和甲基化能力促进新陈代谢并促进脂肪变性和肝损伤 磷脂酰乙醇胺和同型半胱氨酸。为了检验这个假设，我们将鉴定调控的基因 通过样本中的染色质免疫沉淀测序，通过 PPARγ 控制 NASH 中蛋氨酸的使用 用 TZD 治疗的对照小鼠和 PpargΔHep 小鼠（目标 1）。此外，我们将确定 PPARγ 是否直接破坏 使用稳定的方法在对照小鼠原代肝细胞和患有 NASH 的 PpargΔHep 小鼠中使用蛋氨酸 同位素（目标 2）。总的来说，我们将确定肝细胞 PPARγ 如何直接调节蛋氨酸代谢 病理生理条件。该项目的结果将帮助我们在 R01 中开发新方法 针对临床前模型中的特定机制以改善 NASH 逆转的提案。