Irshad, Zehra, Chmel, Nikola Paul, Adya, Raghu and Zammit, Victor A. (2019) Hepatic VLDL secretion : DGAT1 determines particle size but not particle number, which can be supported entirely by DGAT2. Journal of Lipid Research, 60 . pp. 111-120. doi:10.1194/jlr.M089300

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Abstract

We investigated whether, in view of its activity being expressed on both aspects of the endoplasmic reticulum (ER; dual membrane topology), diacylglycerol acyltransferase 1 (DGAT1) plays a distinctive role in determining the triglyceride (TAG) content of VLDL particles secreted by the liver. Mice in which the DGAT1 gene was specifically ablated in hepatocytes (DGAT1-LKO mice) had the same number of VLDL particles (apoB concentration) in the plasma 1 h after Triton 1339 treatment, but these particles were approximately half the size of VLDL particles secreted by control mice and had a proportionately decreased content of TAG, with normal cholesterol and cholesteryl ester contents. Analyses of purified microsomal fractions prepared from 16 h fasted control and DAGT1-LKO mice showed that the TAG/protein ratio in the ER was significantly lower in the latter. Electron micrographs of these livers showed that those from DGAT1-LKO mice did not show the increased lipid content of the smooth ER shown by control livers. The effects of DGAT1- and DGAT2-specific inhibitors on apoB secretion by HepG2 cells showed that DGAT1 is not indispensable for apoB secretion and demonstrated redundancy in the ability of the two enzymes to support apoB secretion. Therefore, our findings show that DGAT1 is essential for the complete lipidation and maturation of VLDL particles within the lumen of the ER, consistent with its dual topology within the ER membrane. In the mouse, DGAT2 can support apoB secretion (particle number) even when TAG availability for full VLDL lipidation is restricted in the absence of DGAT1.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QM Human anatomy Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Science > Chemistry Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Triglycerides, Lipoproteins, Liver -- Metabolism, Cardiovascular system -- Diseases , Metabolic syndrome , Diglycerides
Journal or Publication Title:	Journal of Lipid Research
Publisher:	American Society for Biochemistry and Molecular Biology, Inc.
ISSN:	0022-2275
Official Date:	31 January 2019
Dates:	Date Event 31 January 2019 Published 5 November 2018 Available 6 November 2018 Accepted
Date of first compliant deposit:	13 November 2018
Volume:	60
Page Range:	pp. 111-120
DOI:	10.1194/jlr.M089300
Status:	Peer Reviewed
Publication Status:	Published
Publisher Statement:	This research was originally published in the Journal of Lipid Research. Irshad, Zehra, Chmel, Nikola Paul, Adya, Raghu and Zammit, Victor A. (2019) Hepatic VLDL secretion: DGAT1 determines particle size but not particle number, which can be supported entirely by DGAT2. Journal of Lipid Research, 60 . pp. 111-120. doi:10.1194/jlr.M089300 © the American Society for Biochemistry and Molecular Biology
Access rights to Published version:	Open Access
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID MR/K012819/1 [MRC] Medical Research Council http://dx.doi.org/10.13039/501100000265
Related URLs:	Publisher

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