Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice.
Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, didemnin B, decreases saturated fatty acid overload-induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress-related disease, we hypothesized that acute intervention with didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD). Hyperphagic male ob/ob mice were fed semipurified diet for 4 weeks, and during week 5 received i.p. injections of didemnin B or vehicle on days 1, 4, and 7. Interestingly, we observed that administration of this compound modestly decreased food intake without evidence of illness or distress, and thus included an additional control group matched for food consumption with didemnin B-treated animals. Treatment with didemnin B improved several characteristics of hepatic lipotoxicity to a greater extent than the effects of caloric restriction alone, including hepatic steatosis, and some hepatic markers of ER stress and inflammation (GRP78, Xbp1s, and Mcp1). Plasma lipid and lipoprotein profiles and histopathological measures of NAFLD, including lobular inflammation, and total NAFLD activity score were also improved by didemnin B. These data indicate that acute intervention with the EEF1A inhibitor, didemnin B, improves hepatic lipotoxicity in obese mice with NAFLD through mechanisms not entirely dependent on decreased food intake, suggesting a potential therapeutic strategy for this ER stress-related disease.
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada.
Alexandra M
AM
Hetherington
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada Robarts Research Institute, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada Department of Medicine, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada.
Cynthia G
CG
Sawyez
Robarts Research Institute, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada.
Brian G
BG
Sutherland
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada.
Debra L
DL
Robson
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada.
Rigya
R
Arya
Metabolic and Cardiovascular Diseases Laboratory, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
Karen
K
Kelly
Metabolic and Cardiovascular Diseases Laboratory, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
René L
RL
Jacobs
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada nica.borradaile@schulich.uwo.ca.
Nica M
NM
Borradaile
D000818:Animals; D016923:Cell Death; D047630:Depsipeptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000378:metabolism; D056945:Hep G2 Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D047630:Depsipeptides; D000091342:Endoplasmic Reticulum Chaperone BiP; D005227:Fatty Acids; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007166:Immunosuppressive Agents; D020648:Peptide Elongation Factor 1; C000606749:eEF1A-1 protein, mouse; C030051:didemnins
ER stress; lipids; lipotoxicity; nonalcoholic fatty liver disease; obesity