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％ 在一般人群中。 NAFLD与2型糖尿病密切相关，其中显示出患病率 80％，并且向非酒精性脂肪性肝炎（NASH和NAFLD的提前阶段）进展。迄今为止， NAFLD没有FDA批准的药物治疗。但是，噻唑烷二酮（TZD）， 是有效的抗糖尿病药物，可用于治疗NAFLD/NASH。具体而言，TZD激活过氧化物体 增生剂激活的受体伽马（脂肪细胞，巨噬细胞和肝星状细胞（HSC），PPAR 它们应分别降低胰岛素抵抗，感染和纤维发生。尽管有一些 积极的效果，TZD目前不用于治疗NASH，其真正的潜力可能是抗 纳什药物确实通过对肝细胞功能的直接负作用减少了。实际上，我们的初步 研究表明，肝细胞PPAR是调节肝基因表达的相关因素 有助于NASH的进展，并减少TZD在小鼠肝脏中的治疗作用 纳什。在此提案中，我们假设肝细胞PPAR是 磷脂酰乙醇胺甲基转移酶（PEMT）和黄油蛋白酶甲基 - 摩氏甲基转移酶（BHMT），BHMT）， 破坏新陈代谢，并促进纳什。在我们的目标1中，我们将定义肝细胞的贡献 TZD介导的NASH逆转中的PEMT和BHMT。具体而言，我们将恢复PEMT的表达 或BHMT在纳什（Nash 带有TZD的小鼠逆转NASH。此外，肝细胞PEMT和BHMT将在肝细胞中恢复。 未经TZD处理的PPAR表达的特异性丧失。这个目标将显示PEMT和BHMT如何改善 肝脏健康，并减少脂肪变性，感染和纤维化，以增强TZD的治疗作用 纳什的逆转。在AIM 2中，我们将确定PPAR是否直接破坏了甲基氨酸的代谢 肝细胞。简而言之，我们将在小鼠和人类原发性肝细胞或灌注中使用靶向代谢组学 用TZD处理的对照和肝细胞特异性损失的对照和小鼠的肝脏。这些 实验将确定TZD如何改变在肝细胞中甲基氨酸的使用，并在肝细胞中贡献 特定的pPAR依赖性方式，以维持脂肪变性，感染和纤维化需要积极作用 TZD在脂肪细胞，巨噬细胞和HSC上的of。总体而言，在此提案中，我们将描述肝细胞特定的 pPAR进行调节以促进NAFLD，并限制TZD的潜力 纳什的治疗。该项目的结果将使我们制定理论策略，以增强 使用TZD，并为NAFLD和NASH患者的护理开发新的治疗方法。