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The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease.
Pharmacol Res. 2020 11; 161:105208.PR

Abstract

Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with didemnin B (50 μg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1β secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Robarts Research Institute, Western University, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Group on the Molecular and Cell Biology of Lipids, Department of Agricultural, Food and Nutrition Science, University of Alberta, Edmonton, AB, Canada.Group on the Molecular and Cell Biology of Lipids, Department of Agricultural, Food and Nutrition Science, University of Alberta, Edmonton, AB, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Group on the Molecular and Cell Biology of Lipids, Department of Agricultural, Food and Nutrition Science, University of Alberta, Edmonton, AB, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. Electronic address: nica.borradaile@schulich.uwo.ca.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32977024

Citation

Wilson, Rachel B., et al. "The Marine Compound and Elongation Factor 1A1 Inhibitor, Didemnin B, Provides Benefit in Western Diet-induced Non-alcoholic Fatty Liver Disease." Pharmacological Research, vol. 161, 2020, p. 105208.
Wilson RB, Chen YJ, Sutherland BG, et al. The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease. Pharmacol Res. 2020;161:105208.
Wilson, R. B., Chen, Y. J., Sutherland, B. G., Sawyez, C. G., Zhang, R., Woolnough, T., Hetherington, A. M., Peters, K. M., Patel, K., Kennelly, J. P., Leonard, K. A., Schuurman, M., Jacobs, R. L., Wang, R., & Borradaile, N. M. (2020). The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease. Pharmacological Research, 161, 105208. https://doi.org/10.1016/j.phrs.2020.105208
Wilson RB, et al. The Marine Compound and Elongation Factor 1A1 Inhibitor, Didemnin B, Provides Benefit in Western Diet-induced Non-alcoholic Fatty Liver Disease. Pharmacol Res. 2020;161:105208. PubMed PMID: 32977024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The marine compound and elongation factor 1A1 inhibitor, didemnin B, provides benefit in western diet-induced non-alcoholic fatty liver disease. AU - Wilson,Rachel B, AU - Chen,Yun Jin, AU - Sutherland,Brian G, AU - Sawyez,Cynthia G, AU - Zhang,Richard, AU - Woolnough,Taylor, AU - Hetherington,Alexandra M, AU - Peters,Kia M, AU - Patel,Krisha, AU - Kennelly,John P, AU - Leonard,Kelly-Ann, AU - Schuurman,Meg, AU - Jacobs,René L, AU - Wang,Rennian, AU - Borradaile,Nica M, Y1 - 2020/09/22/ PY - 2020/07/17/received PY - 2020/09/08/revised PY - 2020/09/10/accepted PY - 2020/9/26/pubmed PY - 2021/9/2/medline PY - 2020/9/25/entrez KW - Cell stress KW - EEF1A1 KW - Hepatic steatosis KW - Lipotoxicity KW - Liver fibrosis KW - Liver inflammation SP - 105208 EP - 105208 JF - Pharmacological research JO - Pharmacol Res VL - 161 N2 - Inhibition of eukaryotic elongation factor 1A1 (EEF1A1) with the marine compound didemnin B decreases lipotoxic HepG2 cell death in vitro and improves early stage non-alcoholic fatty liver disease (NAFLD) in young genetically obese mice. However, the effects of didemnin B on NAFLD in a model of long-term diet-induced obesity are not known. We investigated the effects of didemnin B on NAFLD severity and metabolic parameters in western diet-induced obese mice, and on the cell types that contribute to liver inflammation and fibrosis in vitro. Male 129S6 mice were fed either standard chow or western diet for 26 weeks, followed by intervention with didemnin B (50 μg/kg) or vehicle by intraperitoneal (i.p.) injection once every 3 days for 14 days. Didemnin B decreased liver and plasma triglycerides, improved oral glucose tolerance, and decreased NAFLD severity. Moreover, didemnin B moderately increased hepatic expression of genes involved in ER stress response (Perk, Chop), and fatty acid oxidation (Fgf21, Cpt1a). In vitro, didemnin B decreased THP-1 monocyte proliferation, disrupted THP-1 monocyte-macrophage differentiation, decreased THP-1 macrophage IL-1β secretion, and decreased hepatic stellate cell (HSteC) proliferation and collagen secretion under both basal and lipotoxic (high fatty acid) conditions. Thus, didemnin B improves hepatic steatosis, glucose tolerance, and blood lipids in obesity, in association with moderate, possibly hormetic, upregulation of pathways involved in cell stress response and energy balance in the liver. Furthermore, it decreases the activity of the cell types implicated in liver inflammation and fibrosis in vitro. These findings highlight the therapeutic potential of partial protein synthesis inhibition in the treatment of NAFLD. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/32977024/The_marine_compound_and_elongation_factor_1A1_inhibitor_didemnin_B_provides_benefit_in_western_diet_induced_non_alcoholic_fatty_liver_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(20)31516-4 DB - PRIME DP - Unbound Medicine ER -