Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Nica Borradaile

Abstract

Elongation factor 1A-1 (eEF1A-1) was previously identified as a mediator of fatty acid-induced cell death (lipotoxicity) downstream of endoplasmic reticulum (ER) stress. Furthermore, inhibition of the peptide elongation activity of eEF1A-1 with the cyclic depsipeptide didemnin B (DB) diminishes ER stress and lipotoxicity in cultured hepatocytes. Since ER stress is involved in nonalcoholic fatty liver disease (NAFLD), it was hypothesized that administration of DB to obese mice with NAFLD would reduce hepatic lipotoxicity. Treatment with DB for one week improved several parameters associated with hepatic lipotoxicity and modestly decreased food intake without evidence of illness. Liver triglycerides and protein markers of ER stress, plasma measurements of liver enzymes, plasma cholesterol, and glucose homeostasis were all improved. Of these observations, only improved plasma liver enzymes and glucose homeostasis were completely attributed to reduced food intake. It was concluded that acute intervention with DB improved hepatic lipotoxicity in obese mice with NAFLD.