Eukaryotic Elongation Factor 1A1 in Non-Alcoholic Fatty Liver Disease and Metabolism
Abstract
Non-alcoholic fatty liver disease (NAFLD), or, as of recently, metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of chronic liver disease, and affects upwards of 30% of the global population. Importantly, through liver inflammation and fibrosis, NAFLD can progress to cirrhosis and hepatocellular carcinoma. Furthermore, no pharmacological therapies have been approved for the treatment of NAFLD. Previous work has identified a role for eukaryotic elongation factor 1A1 (EEF1A1) in lipotoxicity, a triggering event in the onset of NAFLD, in hepatocyte-like cells. Additionally, inhibition of EEF1A1 with the marine compound didemnin B (DB) improved early NAFLD in a genetic mouse model of obesity. However, the effects of EEF1A1 inhibition with DB on NAFLD in a more clinically relevant mouse model, on cell types that contribute to inflammation and fibrosis in NAFLD, and on other features likely relevant to NAFLD progression, including liver lipid droplet (LD) size, global gene expression, and cellular composition, are uncharacterized. Additionally, several lines of evidence strongly suggest that EEF1A1 has a role in regulating metabolism, but this has not been directly examined. In this thesis, I have demonstrated that, in a western diet-induced obese mouse model of NAFLD, intervention with DB dramatically improves liver steatosis and metabolic parameters, including glucose homeostasis and plasma lipids. Furthermore, DB selectively targets the cell types that would contribute to liver inflammation and fibrosis in NAFLD. I further characterized hepatic changes in the same mouse model to uncover that DB reduces hepatic LD size, alters the hepatic transcriptomic landscape with respect to energy metabolism and proteostasis, and reduces cell type-associated gene expression signatures for several liver cell types with known contributions to NAFLD progression. Finally, using several methods to modulate EEF1A1 expression and activity in cell culture, I uncovered a novel role for EEF1A1 in regulating metabolic substrate utilization. Specifically, EEF1A1 perturbation impairs glycolysis and promotes a switch to oxidative metabolism and fatty acid utilization. Collectively, my work illustrates the involvement of EEF1A1 in NAFLD and metabolism, and underscores the therapeutic potential of targeting EEF1A1 in NAFLD, and more broadly, to favourably alter metabolic substrate utilization in obesity-related conditions.