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Permanent link (DOI): https://doi.org/10.7939/R3057CZ0B

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Roles of Acyl-CoA:Diacylglycerol Acyltransferases 1 and 2 in Triacylglycerol Synthesis and Secretion in Hepatocytes Open Access

Descriptions

Other title
Subject/Keyword
triglycerides
diacylglycerol acyltransferase
hepatocytes
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Li, Chen
Supervisor and department
Lehner, Richard (Pediatrics, Cell Biology)
Examining committee member and department
Zhang, Dawei (Biochemistry, Pediatrics)
Melançon, Paul (Cell Biology)
Rachubinski, Richard (Cell Biology)
Department
Department of Cell Biology
Specialization

Date accepted
2015-07-27T15:23:53Z
Graduation date
2015-11
Degree
Master of Science
Degree level
Master's
Abstract
Triacylglycerol (TG) metabolism with its high-energy potential is stringently regulated. Unbalanced TG regulation, either too much TG that overwhelms cellular storage capacity or too little TG due to defects in adipogenesis, is associated with various metabolic disorders. TG can be exported from liver in very-low density lipoprotein (VLDL). Although compelling evidence suggests that the majority of TG in VLDL is derived from re-esterification of lipolytic products released by endoplasmic reticulum-associated lipases, little is known about the roles of enzymes that catalyze the re-esterification reaction, acyl-CoA:diacylglycerol acyltransferases (DGATs). In mammals, two DGAT enzymes (DGAT1 and DGAT2) with no homology in primary amino acid sequences are encoded by genes belonging to distinct gene families and perform non-redundant physiological functions. The research goal was to investigate the contribution of DGAT1 and DGAT2 to lipid metabolism and lipoprotein secretion in primary mouse and human hepatocytes. Highly selective small-molecule inhibitors of DGAT1 and DGAT2 were used to track storage and secretion of lipids synthesized de novo from [3H]acetic acid and from exogenously supplied [3H]oleic acid. Inactivation of an individual DGAT did not affect incorporation of either radiolabeled precursor into intracellular TG, whereas combined inactivation of both DGATs severely attenuated TG synthesis. However, inhibition of DGAT2 augmented fatty acid oxidation, whereas inhibition of DGAT1 increased TG secretion, suggesting preferential channeling of separate DGAT-derived TG pools to distinct metabolic pathways. Inactivation of DGAT2 impaired cytosolic lipid droplet expansion, whereas DGAT1 inactivation promoted large lipid droplet formation. Moreover, ii inactivation of DGAT2 attenuated expression of lipogenic genes. Finally, TG secretion was significantly reduced upon DGAT2 inhibition without altering extracellular apoB levels. The data suggest that DGAT1 and DGAT2 can compensate for each other to synthesize TG, but TG synthesized by DGAT1 is preferentially channeled to oxidation, while DGAT2 synthesizes TG destined for VLDL assembly.
Language
English
DOI
doi:10.7939/R3057CZ0B
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Chen Li, Lena Li, Jihong Lian, et al. “Roles of Acyl-CoA:Diacylglycerol Acyltransferases 1 and 2 in Triacylglycerol Synthesis and Secretion in Primary Hepatocytes,” Arteriosclerosis, Thrombosis, and Vascular Biology, 35.5 (2015): 1080-1091.

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