PPARgamma-regulated mechanisms in hepatocytes that promote NAFLD

肝细胞中 PPARgamma 调节机制促进 NAFLD

• 批准号: 10557828
• 负责人: Jose Cordoba-Chacon
• 金额: $ 41.6万
• 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/10557828
• 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; Hepatic Tissue; Hepatocyte; Homocysteine; Human; In Vitro; Inflammation; Insulin Resistance; Knock-out; Label; Lecithin; Lipids; Liver; Macrophage; Mediating; Messenger RNA; Methionine; Methionine Metabolism Pathway; Methylation; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PPAR gamma; Patients; Perfusion; Pharmaceutical Preparations; Pharmacological Treatment; Phosphatidylethanolamine N-Methyltransferase; Prevalence; Regulation; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; 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; 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 (PPARγ) 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 PPARγ 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 PPARγ 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 PPARγ-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 PPARγ 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 PPARγ 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 PPARγ 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 PPARγ-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 PPARγ 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