Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Elongation factor (EEF) 1A1 is expressed in liver, pancreas, and brain, and participates in protein synthesis by promoting aa-tRNA-ribosome binding. EEF1A1 also has ‘moonlighting’ functions in actin cytoskeleton regulation, and in apoptosis/anoikis in response to stress. Whether both the canonical and non-canonical functions of EEF1A1 are involved in cellular responses to metabolic stress is unclear. The goal of this program is to elucidate the links between protein synthesis, regulation of the actin cytoskeleton, and cellular stress responses induced by lipid overload. Lipotoxicity is the process whereby ectopic lipid deposition in non-adipose cells leads to cellular dysfunction, cell death, and eventual tissue dysfunction. Since many lipid metabolic processes occur at the ER, lipotoxic conditions in secretory cell types are accompanied by rapid induction of ER stress and the unfolded protein response (UPR). The UPR restores homeostasis by halting protein synthesis, while promoting protein folding and degradation. However, severe or prolonged stress initiates an ER stress response (ERSR) which can lead to cell death. The ERSR involves re-initiation of protein synthesis to generate pro-inflammatory and pro-apoptotic factors – a deleterious anabolic response. EEF1A1 is induced in upon ER stress, and is known to be a key mediator of lipotoxic cell death. We recently found that blocking the protein synthetic activity of EEF1A1 with a specific inhibitor, didemnin B, decreased lipotoxic cell death in hepatocytes. Moreover, acute intervention with didemnin B improved hepatic ER stress and associated inflammation in mice with severe fatty liver. But the precise mechanisms through which EEF1A1 participates in cellular stress responses and promotes hepatocyte lipotoxicity are unclear. It is also not known whether EEF1A1 participates in lipotoxicity in other ER-rich cell types, particularly pancreatic beta-cells. Thus the short term objectives of this program are to determine the comparative functions of EEF1A1 in cellular responses to excess lipid accumulation (1) in cultured hepatocytes and pancreatic beta-cells, and (2) in liver and pancreas of mice with diet-induced tissue lipid accumulation. The long term program goal is to understand the global mechanism(s) of action of EEF1A1 in cellular stress responses to excess lipid in metabolic tissues throughout the body, including liver, pancreas, myocardium, and skeletal muscle, in part by using a unique transgenic Eef1a1 -EGFP mouse model to test whole body Eef1a1 expression patterns in response to metabolic stress induced by high fat diet. Overall, this program will determine how the canonical and non-canonical functions of EEF1A1 are involved in ER stress response and cell death processes induced by excessive cellular lipid accumulation, thereby furthering our understanding of lipotoxicity and the diverse functions of EEF1A1.