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

肥胖与许多慢性和进行性疾病的风险增加有关，肥胖相关的代谢性疾病构成了重大的公共卫生负担。人们早就知道，肥胖与2型糖尿病的风险增加有关，这是由于对胰岛素作用的抵抗而引起的。在过去的几年里，人们越来越意识到肥胖与肝实质脂质积累密切相关（非酒精性脂肪性肝病（NAFLD））。NAFLD包括肝脂肪变性（肝细胞胞质内中性脂质积聚）和更严重的非酒精性脂肪性肝炎（NASH）（与脂肪变性病变相关的肝脏炎症和纤维化）。相当比例的NAFLD和NASH患者会发展为肝硬化和肝功能衰竭，并且发展为肝细胞癌的风险增加。NASH目前是一种未经批准治疗的疾病，构成了一个重大的未满足的医疗需求。目前的治疗发展集中在靶向纤维化或旨在降低肝脏脂质含量的药物上。在迄今为止的临床试验中，已知是PPARγ核受体配体的胰岛素致敏噻唑烷二酮类药物（TZDs）对NASH的作用是所有实验药物中最强的。在此资助的前一阶段，我们测试了TZDs也参与和抑制线粒体丙酮酸载体（MPC）的新假设。事实上，我们发现下一代TZD （MSDC-0602）参与MPC，但在小鼠模型中明显减弱了激活PPARγ的能力，减少了星状细胞激活和其他NASH终点。此外，肝细胞特异性MPC缺失的小鼠不会发生胰岛素抵抗、糖尿病和NASH。基于这一数据和其他实验数据，MSDC-0602被推进到为期一年的2b期临床试验（EMMINENCE: NCT02784444）。在之前的支持期间，我们还确定了一些作为MPC抑制剂的候选化合物，并有初步数据表明这些抑制剂也能改善胰岛素敏感性。虽然现在有很好的证据支持靶向MPC是治疗NASH的可行治疗方法这一关键前提，但关于MPC抑制导致有益代谢和抗纤维化作用的分子机制仍存在许多问题。此外，以前的工作主要集中在肝细胞中的MPC；对星状细胞的影响，而星状细胞对NASH的发展至关重要，尚未被探索。该应用有3个主要目标：验证新型MPC抑制剂将改善小鼠胰岛素敏感性和NASH终点的假设。目的：梳理MPC调节剂对胰岛素抵抗和NASH终点作用的分子机制。[3]验证针对星状细胞中的MPC有助于MPC抑制剂的有益作用的假设。该应用的首要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。这些研究将确定分子机制，并提供概念验证证据，支持未来的临床试验，以测试这些药物对糖尿病、NASH和其他肥胖相关心脏代谢疾病患者的疗效。

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.