PPARgamma-regulated mechanisms in hepatocytes that promote NAFLD

肝细胞中 PPARgamma 调节机制促进 NAFLD

• 批准号: 10338941
• 负责人: Jose Cordoba-Chacon
• 金额: $ 47.85万
• 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: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338941
• 关键词: Adipocytes; Adult; Anti-Inflammatory Agents; Caring; Cells; Cholesterol; Data; Dependovirus; Development; Diet; Disease; Dose; Enzymes; Extrahepatic; FDA approved; Fatty acid glycerol esters; Fibrosis; Fructose; Gene Expression; General Population; Health; Healthcare Systems; Hepatic; Hepatic Stellate Cell; Hepatocyte; Homocysteine; Human; In Vitro; Inflammation; Insulin Resistance; Knock-out; Label; Lead; Lecithin; Lipids; Liver; Mediating; Messenger RNA; Methionine; Methionine Metabolism Pathway; Methylation; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PPAR alpha; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacological Treatment; Phosphatidylethanolamine N-Methyltransferase; Prevalence; Regulation; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Tissues; Very low density lipoprotein; betaine-homocysteine methyltransferase; chronic liver disease; clinical care; clinically relevant; defined contribution; diabetogenic; expectation; experimental study; fibrogenesis; improved; in vivo; innovation; liver injury; macrophage; metabolomics; methyl group; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; restoration

PROJECT SUMMARY / ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease with a prevalence of 25% in the general population. NAFLD is strongly associated with type 2 diabetes, where it shows a prevalence up to 80%, and a strong progression to non-alcoholic steatohepatitis (NASH, and advance stage of NAFLD). To date, there are no FDA-approved pharmacological treatments for NAFLD. However, thiazolidinediones (TZD), which are effective anti-diabetogenic drugs, may be used to treat NAFLD/NASH. Specifically, TZD activate peroxisome proliferator-activated receptor gamma (PPAR in adipocytes, macrophages, and hepatic stellate cells (HSC), and they should reduce insulin resistance, inflammation, and fibrogenesis, respectively. Despite having some positive effects, TZD are not currently used to treat NASH, and it is possible that their true potential as anti- NASH drugs are indeed reduced by direct negative actions on hepatocyte function. In fact, our preliminary studies show that hepatocyte PPAR is a relevant factor in the regulation of hepatic gene expression that contributes to the progression of NASH, and reduces the therapeutic effects of TZD in the liver of mice with NASH. In this proposal, we hypothesize that hepatocyte PPAR is a negative regulator of phosphatidylethanolamine methyltransferase (PEMT) and betaine-homocysteine methyltransferase (BHMT), disrupts methionine metabolism, and promotes NASH. In our Aim 1, we will define the contribution of hepatocyte PEMT and BHMT in the TZD-mediated reversal of NASH. Specifically, we will restore the expression of PEMT or BHMT with adeno-associated viruses in PPAR-intact mice after the development of NASH and treat these mice with TZD to reverse NASH. Also, hepatocyte PEMT and BHMT will be restored in mice with hepatocyte- specific loss of PPAR expression without a TZD treatment. This aim will show how PEMT and BHMT improve liver health, and reduce steatosis, inflammation and fibrosis to enhance the therapeutic actions of TZD in the reversal of NASH. In aim 2, we will determine if PPAR directly disrupts the metabolism of methionine in hepatocytes. Briefly, we will use targeted metabolomics in mouse and human primary hepatocytes or in perfused livers of controls and mice with hepatocyte-specific loss of PPAR expression that are treated with TZD. These experiments will identify how TZD alters the use of methionine in hepatocytes, and contributes, in a hepatocyte- specific PPAR-dependent manner, to sustain steatosis, inflammation and fibrosis despite the positive actions of TZD on adipocytes, macrophages, and HSC. Overall, in this proposal we will describe how hepatocyte-specific PPARnegatively regulates methionine metabolism to promote NAFLD, and to limit the potential of TZD as a therapy for NASH. The outcomes of this project will lead us to develop therapeutic strategies that enhance the use of TZD, and to develop new treatments for NAFLD and the care of NASH patients.

项目概要/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% 在一般人群中。 NAFLD 与 2 型糖尿病密切相关，其患病率高达 80%，并且严重进展为非酒精性脂肪性肝炎（NASH，以及 NAFLD 的晚期）。迄今为止， 目前尚无 FDA 批准的 NAFLD 药物治疗方法。然而，噻唑烷二酮类（TZD） 是有效的抗糖尿病药物，可用于治疗 NAFLD/NASH。具体来说，TZD 激活过氧化物酶体 增殖剂激活受体 γ（脂肪细胞、巨噬细胞和肝星状细胞 (HSC) 中的 PPAR， 它们应该分别减少胰岛素抵抗、炎症和纤维形成。尽管有一些 TZD 目前尚未用于治疗 NASH，但其作为抗非酒精性脂肪性肝炎 (NASH) 的真正潜力可能是存在的。 NASH 药物确实可以通过对肝细胞功能的直接负面作用而减少。事实上，我们初步 研究表明，肝细胞PPAR是调节肝脏基因表达的相关因子， 促进 NASH 的进展，并降低 TZD 在小鼠肝脏中的治疗效果 纳什。在这个提议中，我们假设肝细胞 PPAR 是一个负调节因子 磷脂酰乙醇胺甲基转移酶（PEMT）和甜菜碱-同型半胱氨酸甲基转移酶（BHMT）， 扰乱蛋氨酸代谢，促进 NASH。在我们的目标 1 中，我们将定义肝细胞的贡献 PEMT 和 BHMT 在 TZD 介导的 NASH 逆转中的作用。具体来说，我们将恢复PEMT的表达 或 BHMT 与腺相关病毒在 PPAR- 完整小鼠中发生 NASH 后进行治疗 小鼠用 TZD 逆转 NASH。此外，肝细胞 PEMT 和 BHMT 将在肝细胞- 未经 TZD 治疗，PPAR 表达特异性丧失。该目标将展示 PEMT 和 BHMT 如何改进 肝脏健康，减少脂肪变性、炎症和纤维化，增强 TZD 在肝脏中的治疗作用 NASH 的逆转。在目标 2 中，我们将确定 PPAR 是否直接破坏体内蛋氨酸的代谢 肝细胞。简而言之，我们将在小鼠和人类原代肝细胞或灌注肝细胞中使用靶向代谢组学 使用 TZD 治疗的对照组和肝细胞特异性 PPAR-表达缺失小鼠的肝脏。这些 实验将确定 TZD 如何改变肝细胞中蛋氨酸的使用，并在肝细胞中做出贡献 尽管有积极作用，但仍以特定的 PPAR 依赖性方式维持脂肪变性、炎症和纤维化 TZD 对脂肪细胞、巨噬细胞和 HSC 的作用。总的来说，在本提案中，我们将描述肝细胞特异性如何 PPAR——负向调节蛋氨酸代谢，促进 NAFLD，并限制 TZD 作为治疗药物的潜力 NASH 的治疗。该项目的成果将引导我们制定治疗策略，以增强 使用 TZD，并开发 NAFLD 的新疗法和 NASH 患者的护理。