Targeting the mitochondrial pyruvate carrier to treat insulin resistance and nonalcoholic fatty liver disease

靶向线粒体丙酮酸载体治疗胰岛素抵抗和非酒精性脂肪肝

基本信息

批准号：
10533376
负责人：
Brian N Finck
金额：
$ 42.85万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533376
关键词：
Affect Attenuated Automobile Driving Awareness Branched-Chain Amino Acids Carbohydrates Cardiometabolic Disease Cellular Metabolic Process Chronic Chronic Disease Cirrhosis Clinical Clinical Trials Cytosol Data Development Diabetes Mellitus Disease Drug Targeting Drug usage Fatty Liver Fatty acid glycerol esters Fibrosis Future Genetic Genetic Models Goals Grant Hepatic Hepatic Stellate Cell Hepatocyte Insulin Insulin Resistance Lesion Ligands Link Lipids Liver Liver Failure Liver Fibrosis Liver parenchyma Mediating Medical Metabolic Metabolic Diseases Metabolism Mitochondria Molecular Molecular Mechanisms of Action Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity PPAR gamma Patients Pharmaceutical Preparations Pharmacologic Substance Phase Play Primary carcinoma of the liver cells Progressive Disease Public Health Pyruvate Metabolism Pathway Resistance Risk Stimulus Testing Therapeutic Thiazolidinediones Work attenuation clinical development drug efficacy efficacy testing genetic inhibitor improved inhibitor insulin sensitivity insulin sensitizing drugs liver inflammation mouse model next generation non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutics pyruvate carrier response stellate cell therapeutic development zaprinast

项目摘要

Obesity is associated with an increased risk of a number of chronic and progressive diseases and obesity-related metabolic diseases constitute a significant public health burden. It has long been known that obesity is linked to increased risk of type 2 diabetes precipitated by resistance to the effects of insulin. Over the past few years, there is also increased awareness that obesity is strongly associated with accumulation of lipid in the liver parenchyma (nonalcoholic fatty liver disease (NAFLD)). The term, NAFLD, encompasses both hepatic steatosis (the accumulation of neutral lipid within the cytosol of hepatocytes) and the more severe nonalcoholic steatohepatitis (NASH) (hepatic inflammation and fibrosis associated with steatotic lesions). A significant proportion of NAFLD and NASH patients will progress to cirrhosis and liver failure and are at increased risk for developing hepatocellular carcinoma. NASH is currently a disease without an approved treatment and constitutes a significant unmet medical need. Current therapeutic development is focused on drugs that either target fibrosis or aim to reduce hepatic lipid content. In clinical trials to date, insulin-sensitizing thiazolidinediones (TZDs) known to be ligands for the PPARγ nuclear receptor have shown some of the strongest effects on NASH of any experimental drugs. In the previous period of support provided by this grant, we tested the novel hypothesis that TZDs also engage and inhibit the mitochondrial pyruvate carrier (MPC). Indeed, we found that a next generation TZD (MSDC-0602) that engaged the MPC, but had markedly attenuated ability to activate PPARγ, reduced stellate cell activation and other NASH endpoints in a mouse model. Moreover, mice with hepatocyte-specific MPC deletion were protected from developing insulin resistance, diabetes, and NASH. On the strength of this and other experimental data, MSDC-0602 was advanced to a one-year, Phase 2b clinical trial (EMMINENCE: NCT02784444). During the previous period of support, we also identified a number of candidate compounds that act as MPC inhibitors and have preliminary data that these inhibitors also improve insulin sensitivity. Although there is now good evidence supporting the key premise that targeting the MPC is a viable therapeutic approach for treating NASH, many questions remain regarding the molecular mechanisms by which MPC inhibition leads to beneficial metabolic and anti-fibrotic effects. In addition, previous work has primarily focused on the MPC in hepatocytes; the effects on stellate cells, which are critical to the development of NASH, have not been explored. This application has 3 overarching goals: [1] To test the hypothesis that novel MPC inhibitors will improve insulin sensitivity and NASH endpoints in mice. [2] To tease apart the molecular mechanisms of action of MPC modulators on insulin resistance and NASH endpoints. [3] To test the hypothesis that targeting the MPC in stellate cells contributes to the beneficial effects of MPC inhibitors. The overarching premise of this application is that targeting the MPC in hepatocytes and stellate cells will be useful for treating insulin resistance and NASH. These studies will define molecular mechanisms and provide proof-of-concept evidence supporting future clinical trials to test the efficacy of these drugs in patients with diabetes, NASH, and other obesity-related cardiometabolic diseases.

肥胖与许多慢性和进行性疾病的风险增加有关，而与肥胖相关的代谢疾病构成了重大的公共健康负担。人们早就知道，肥胖与2型糖尿病的风险增加有关，而这种风险是由对肥胖的抵抗力引起的。在过去的几年中，人们越来越认识到肥胖与肝实质中的脂质积累密切相关（非酒精性脂肪肝疾病（NAFLD））。脂肪变性（肝细胞胞浆内中性脂质的积累）和更严重的非酒精性脂肪性肝炎（NASH）（与脂肪病变相关的肝脏炎症和纤维化）很大一部分 NAFLD 和 NASH 患者将进展为肝硬化和肝功能衰竭。 NASH 是一种尚未获得批准的治疗方法的疾病，目前的治疗开发主要集中在针对以下任一药物的治疗上。迄今为止的临床试验中，作为 PPARγ 核受体配体的胰岛素增敏噻唑烷二酮类药物 (TZD) 已显示出对 NASH 的最强效果。在这笔资金的支持下，我们测试了 TZD 也参与并抑制线粒体丙酮酸载体 (MPC) 的新假设，事实上，我们发现了下一代 TZD。 (MSDC-0602) 与 MPC 结合，但在小鼠模型中激活 PPARγ 的能力显着减弱，星状细胞激活和其他 NASH 终点减少。此外，肝细胞特异性 MPC 缺失的小鼠免受胰岛素抵抗、糖尿病和糖尿病的影响。 NASH。根据这一数据和其他实验数据，MSDC-0602 已进入为期一年的 2b 期临床试验（EMMINENCE： NCT02784444）。在之前的支持期间，我们还鉴定了许多充当 MPC 抑制剂的候选化合物，并有初步数据表明这些抑制剂也可以改善胰岛素敏感性，尽管现在有充分的证据支持靶向 MPC 的关键前提。虽然 MPC 是治疗 NASH 的可行治疗方法，但关于 MPC 抑制有益代谢和抗纤维化作用的分子机制仍然存在许多问题。对于 NASH 的发展至关重要的星状细胞尚未得到探索。该应用有 3 个总体目标：[1] 测试新型 MPC 抑制剂将改善小鼠的胰岛素敏感性和 NASH 终点的假设。分离 MPC 调节剂对胰岛素抵抗和 NASH 终点的作用分子机制 [3] 检验针对星状细胞中的 MPC 有助于 MPC 抑制剂的总体有益作用的假设。该应用的前提是，靶向肝细胞和星状细胞中的 MPC 将有助于治疗胰岛素抵抗和 NASH。这些研究将定义分子机制，并提供支持未来临床试验的概念验证证据，以测试这些药物在治疗中的功效。患有糖尿病、NASH 和其他与肥胖相关的心脏代谢疾病的患者。