Macrophage Mitochondrial Pyruvate Carrier in Nonalcoholic Steatohepatitis

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Project Summary Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is a leading cause of liver-related morbidity and mortality. Having NASH greatly increases the risk of developing end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Despite the healthcare burden, there are no licensed drug therapies for NASH. NASH presents as hepatocyte damage, inflammation, and varying degrees of fibrosis, but the distinct mechanisms that drive this progression are unclear. However, evidence shows that infiltrating macrophages play a pivotal role in NASH progression. Macrophages are innate immune cells that can polarize into inflamma- tory phenotypes that exacerbate hepatic injury, or into resolving phenotypes that can mediate liver repair. Yet the mechanisms driving macrophage polarity in NASH progression are undefined. There is a critical need to understand the processes that dictate macrophage polarization in NASH progression in order to identify thera- peutic targets that decrease the burden of NASH. Our long-term goal is to understand the metabolic regulatory mechanisms dictating macrophage polariza- tion to develop treatments for NASH and its associated comorbidities. Importantly, macrophage polarization results in the metabolic rewiring of mitochondrial metabolism. This is not only a consequence of the polariza- tion process, but the accumulation of specific tricarboxylic acid (TCA) cycle-derived intermediates profoundly influences inflammatory and anti-inflammatory gene expression in macrophages. A central player in mitochon- drial metabolism is the mitochondrial pyruvate carrier (MPC), which transports pyruvate, a primary product of glycolysis, into the mitochondrial matrix where it can enter the TCA cycle. Previous evidence shows MPC inhi- bition alters intracellular TCA metabolites in metabolic cells like myocytes and hepatocytes, but the effect on macrophages is unknown. Furthermore, our lab has shown that novel MPC inhibitors currently used in clinical trials effectively reduce NASH in mice. Importantly, the effect of MPC inhibition in macrophages is undefined. Given the significance of intermediary metabolism in macrophage activation, and the significant role of the MPC in mitochondrial metabolism, the primary objective of this application is to [1] identify the mechanisms by which MPC contributes to macrophage activation and polarization, and [2] determine how specific deletion of MPC in macrophages influences NASH progression. Our central hypothesis is that MPC inhibition in mono- cyte-derived macrophages will reduce the inflammatory response and mitigate NASH development. Comple- tion of these studies will contribute to the understanding of mitochondrial metabolism in macrophage function and NASH progression, and highlight the clinical utility of macrophages in NASH.