Thesis Format

Integrated Article

Eukaryotic Elongation Factor 1A1 in Non-Alcoholic Fatty Liver Disease and Metabolism

Author

Rachel B. Wilson, Western UniversityFollow

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Borradaile, Nica M.

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.

Summary for Lay Audience

Fatty liver disease, or non-alcoholic fatty liver disease (NAFLD), which is caused by fat build-up in the liver, is the most common chronic liver disease and affects nearly one third of the global population. NAFLD is linked to being overweight or obese, because the excess fat in the body spills over into the liver. Because NAFLD can progress to liver cirrhosis and liver cancer, and there is currently no drug to treat NAFLD, there is a lot of interest in learning more about proteins that may be involved in NAFLD and could potentially be targeted by drugs to treat NAFLD. A protein involved in making other proteins, eukaryotic elongation factor 1A1 (EEF1A1), is involved in the liver injury that happens in NAFLD. And, blocking EEF1A1 with a marine compound called didemnin B (DB) improved NAFLD in mice with a genetic mutation that causes them to become obese and get NAFLD. But, it’s not known whether DB has a similar effect in mice that get NAFLD from high-fat feeding, which better mimics how humans develop NAFLD. Also, the effects of DB on events that happen in the liver during NAFLD progression are unknown. Finally, EEF1A1 may control how cells generate energy, but this hasn’t been directly studied. In this thesis, I showed that blocking EEF1A1 with DB improved NAFLD in mice which became obese by eating a high-fat diet. I also showed that DB targets cell types that would be involved in NAFLD progressing to more severe disease, like cirrhosis and liver cancer. In further examining the livers of mice treated with DB, I showed that DB improved several aspects of liver function that typically worsen during NAFLD progression. Finally, I showed that EEF1A1 controls how cells generate energy. Specifically, I showed that, when EEF1A1 is blocked, cells are less likely to use sugar and are more likely to use fat to generate energy. As a whole, my work has shown that EEF1A1 is involved in NAFLD and affects how cells generate energy, and that blocking EEF1A1 with DB helps improve many aspects of NAFLD in mice.

Recommended Citation

Wilson, Rachel B., "Eukaryotic Elongation Factor 1A1 in Non-Alcoholic Fatty Liver Disease and Metabolism" (2023). Electronic Thesis and Dissertation Repository. 9805.
https://ir.lib.uwo.ca/etd/9805