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

• 批准号: 10333375
• 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
• 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/10333375
• 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; Peroxisome Proliferator-Activated Receptors; 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; base; 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

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.

肥胖与多种慢性和进行性疾病的风险增加有关，与肥胖相关的代谢疾病构成了重要的公共卫生伯恩伦。长期以来，众所周知，肥胖与抗胰岛素作用抗性的2型糖尿病风险增加有关。在过去的几年中，人们对肥胖症在肝实质（非酒精性脂肪肝病（NAFLD））中的积累密切相关。 NAFLD术语既包含肝脂肪变性（肝胞质中中性脂质的积累）和更严重的非酒精脂肪变性（NASH）（NASH）（肝炎炎症和与脂肪酸病变相关的纤维化）。 NAFLD和NASH患者中很大一部分将发展为肝硬化和肝衰竭，并有增加肝细胞癌的风险。纳什目前是一种没有批准治疗的疾病，构成了巨大的未满足医疗需求。当前的治疗发育集中在靶向纤维化或旨在减少肝脂质含量的药物上。在迄今为止的临床试验中，已知为PPARγ核受体的配体的胰岛素敏化硫胆苷（TZD）表明，对任何实验药物的NASH都有一些强大的影响。在该赠款提供的上一个支持阶段，我们检验了新的假设，即TZD还可以参与并抑制线粒体丙酮酸载体（MPC）。确实，我们发现接合MPC的下一代TZD（MSDC-0602），但已明显减弱激活PPARγ的能力，减少了小鼠模型中的星状细胞激活和其他NASH端点。此外，可以保护具有肝细胞特异性MPC缺失的小鼠免受胰岛素抵抗，糖尿病和NASH的发展。根据此和其他实验数据的强度，MSDC-0602已提高到一年的2B期临床试验（Eminence：NCT02784444）。在上一个支持期间，我们还确定了许多充当MPC抑制剂的候选化合物，并具有初步数据，即这些抑制剂也可以提高胰岛素敏感性。尽管现在有充分的证据支持关键前提，即靶向MPC是一种可行的治疗方法，但有关MPC抑制导致有益代谢和抗纤维化作用的分子机制仍然存在许多问题。此外，先前的工作主要集中在肝细胞中的MPC上。尚未探索对NASH发展至关重要的星状细胞的影响。该应用具有3个总体目标：[1]测试新型MPC抑制剂将改善小鼠胰岛素敏感性和NASH终点的假设。 [2]嘲笑MPC调节剂对胰岛素耐药性和NASH终点的作用的分子机制。 [3]检验以下假设：靶向星状细胞中的MPC有助于MPC抑制剂的有益作用。该应用程序的总体前提是靶向肝细胞和星状细胞中的MPC将有用。胰岛素抵抗和NASH。这些研究将定义分子机制，并提供概念验证证据，以支持未来的临床试验，以测试这些药物在糖尿病，纳什和其他与肥胖相关的心脏测定疾病中的有效性。