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

肥胖与一些慢性和进行性疾病的风险增加有关，与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型糖尿病风险的增加有关，2型糖尿病的风险增加是由于对胰岛素的影响产生抵抗。在过去的几年里，人们也越来越多地意识到肥胖与肝实质中脂质的积累(非酒精性脂肪性肝病)密切相关。NAFLD包括肝脏脂肪变性(中性脂肪在肝细胞胞浆中积聚)和更严重的非酒精性脂肪性肝炎(NASH)(与脂肪变性损害相关的肝脏炎症和纤维化)。相当大比例的NAFLD和NASH患者将进展为肝硬变和肝功能衰竭，并增加发展为肝细胞癌的风险。NASH目前是一种没有得到批准的治疗的疾病，构成了一个重大的未得到满足的医疗需求。目前的治疗进展集中在针对纤维化或旨在降低肝脂含量的药物上。在迄今为止的临床试验中，已知的PPARγ核受体配体的胰岛素敏感型噻唑烷二酮(TZD)对NASH的影响是所有实验药物中最强的。在这笔赠款提供的前一期支持中，我们测试了TZDS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，在小鼠模型中，下一代TZD(MSDC0602)可以激活MPC，但显著减弱激活PPARγ的能力，减少星状细胞激活和其他NASH端点。此外，肝细胞特异性MPC缺失的小鼠可以预防发生胰岛素抵抗、糖尿病和NASH。在此和其他实验数据的支持下，MSDC-0602被推进到为期一年的2b期临床试验(EMMINCE：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可以改善胰岛素敏感性。尽管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抑制导致有益的代谢和抗纤维化作用的分子机制仍然存在许多问题。此外，以前的工作主要集中在肝细胞中的MPC；对NASH发展至关重要的星状细胞的影响尚未被探索。这项应用有3个主要目标：[1]测试新的MPC抑制剂将改善小鼠胰岛素敏感性和NASH终点的假设。[2]梳理MPC调节剂在胰岛素抵抗和NASH终点中作用的分子机制。[3]为了验证靶向星状细胞中的MPC有助于MPC抑制剂的有益效果的假设。这一应用的首要前提是，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性疾病患者的疗效。

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.