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.

项目总结/摘要 非酒精性脂肪性肝病（NAFLD）是慢性肝病的主要原因，患病率为25% 在普通人群中的比例。NAFLD与2型糖尿病密切相关，其患病率高达 80%，并且强烈进展为非酒精性脂肪性肝炎（NASH和晚期NAFLD）。到目前为止， 对于NAFLD没有FDA批准的药物治疗。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 脂肪细胞、巨噬细胞和肝星状细胞（HSC）中的增殖物激活受体γ（PPAR γ）， 它们应该分别减少胰岛素抵抗、炎症和纤维化。尽管拥有一些 积极的作用，TZD目前还没有用于治疗NASH，有可能它们作为抗NASH药物的真正潜力， NASH药物确实通过对肝细胞功能的直接负面作用而减少。事实上，我们初步的 研究表明，肝细胞的过氧化物酶体增殖物激活受体是调节肝基因表达的相关因子， 促进NASH的进展，并降低TZD在患有NASH的小鼠的肝脏中的治疗效果。 纳什在这个建议中，我们假设肝细胞的过氧化物酶体增殖物激活受体是一个负调节因子， 磷脂酰乙醇胺甲基转移酶（PEMT）和甜菜碱-高半胱氨酸甲基转移酶（BHMT）， 破坏甲硫氨酸代谢并促进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 γ-完整小鼠中的NASH发展后， 用TZD逆转NASH。此外，肝细胞PEMT和BHMT将在具有肝细胞- 没有TZD处理的情况下，PPAR γ表达的特异性损失。这一目标将显示如何PEMT和BHMT改善 肝脏健康，并减少脂肪变性，炎症和纤维化，以增强TZD在 NASH逆转。在目标2中，我们将确定PPAR γ是否直接破坏了蛋氨酸的代谢， 肝细胞简而言之，我们将在小鼠和人原代肝细胞或灌注的 对照组和用TZD处理的肝细胞特异性丧失PPAR γ表达的小鼠的肝脏。这些 实验将确定TZD如何改变肝细胞中甲硫氨酸的使用，并有助于肝细胞- 特异性的PPAR γ依赖性的方式，以维持脂肪变性，炎症和纤维化，尽管积极的行动， TZD对脂肪细胞、巨噬细胞和HSC的影响。总之，在本提案中，我们将描述肝细胞特异性 过氧化物酶体增殖物激活物受体拮抗剂负性调节蛋氨酸代谢，促进非酒精性脂肪肝，并限制TZD作为抗脂肪肝药物的潜力。 治疗NASH。该项目的结果将引导我们制定治疗策略， TZD的使用，并开发NAFLD的新治疗方法和NASH患者的护理。