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

点击翻译按钮获取中文摘要

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.