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Evidence that diacylglycerol acyltransferase 1 (DGAT1) has dual membrane topology in the endoplasmic reticulum of HepG2 cells

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Wurie, Haja R., Buckett, L., Zammit, Victor A. and UNSPECIFIED. (2011) Evidence that diacylglycerol acyltransferase 1 (DGAT1) has dual membrane topology in the endoplasmic reticulum of HepG2 cells. Journal of Biological Chemistry, Vol.286 (No.42). pp. 36238-36247. ISSN 0021-9258

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Abstract

Triacylglycerol (TAG) synthesis and secretion are important functions of the liver which have major impacts on health, as over-accumulation of TAG within the liver (steatosis) or hypersecretion of TAG within very-low-density lipoproteins (VLDL) both have deleterious metabolic consequences. Two diacylglycerol acyltransferases (DGATs 1 and 2) can catalyse the final step in the synthesis of TAG from diacylglycerol (DAG) which has been suggested to play an important role in the transfer of the glyceride moiety across the endoplasmic reticular membrane for (re)synthesis of TAG on the lumenal aspect of the endoplasmic reticular (ER) membrane [Owen, M., Corstorphine, C.G., and V.A. Zammit (1997) Biochem. J. 323, 17-21 ]. Recent topographical studies suggested that the oligomeric enzyme DGAT1 is exclusively lumen-facing (latent) in the ER membrane. By contrast, in the present study, using two specific inhibitors of human DGAT1, we present evidence that DGAT1 has a dual topology within the ER of HepG2 cells, with approximately equal DGAT1 activities exposed on the cytosolic and lumenal aspects of the ER membrane. This was confirmed by the observation of the loss of both overt (partial) and latent (total) DGAT activity in microsomes prepared from livers of Dgat1 -/- mice. Conformational differences between DGAT1 molecules having the different topologies were indicated by the markedly different sensitivities of the overt DGAT1 to one of the inhibitors. These data suggest that DGAT1 belongs to the family of oligomeric membrane proteins that adopt a dual membrane topology.

Item Type: Journal Article
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QR Microbiology
R Medicine > RC Internal medicine
Divisions: Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Diglycerides, Acyltransferases, Insulin resistance, Endoplasmic reticulum
Journal or Publication Title: Journal of Biological Chemistry
Publisher: The American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Official Date: 21 October 2011
Volume: Vol.286
Number: No.42
Page Range: pp. 36238-36247
Identification Number: 10.1074/jbc.M111.251900
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Funder: Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), AstraZeneca (Firm)
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URI: http://wrap.warwick.ac.uk/id/eprint/39720

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