Document Detail


The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and -2.
MedLine Citation:
PMID:  22493088     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride (TG) synthesis. There are two isoforms, DGAT1 and DGAT2, with distinct protein sequences and potentially different physiological functions. To date, the ability to determine clear functional differences between DGAT1 and DGAT2, especially with respect to hepatic TG synthesis, has been elusive. To dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with (13)C(3)-D(5)-glycerol or (13)C(18)-oleic acid, and profiled the major isotope-labeled TG species by liquid chromatography tandem mass spectrometry. Selective DGAT1 and DGAT2 inhibitors demonstrated that (13)C(3)-D(5)-glycerol-incorporated TG synthesis was mediated by DGAT2, not DGAT1. Conversely, (13)C(18)-oleoyl-incorporated TG synthesis was predominantly mediated by DGAT1. To trace hepatic TG synthesis and VLDL triglyceride (VLDL-TG) secretion in vivo, we administered D(5)-glycerol to mice and measured plasma levels of D(5)-glycerol-incorporated TG. Treatment with an antisense oligonucleotide (ASO) to DGAT2 led to a significant reduction in D(5)-glycerol incorporation into VLDL-TG. In contrast, the DGAT2 ASO had no effect on the incorporation of exogenously administered (13)C(18)-oleic acid into VLDL-TG. Thus, our results indicate that DGAT1 and DGAT2 mediate distinct hepatic functions: DGAT2 is primarily responsible for incorporating endogenously synthesized FAs into TG, whereas DGAT1 plays a greater role in esterifying exogenous FAs to glycerol.
Authors:
Jenson Qi; Wensheng Lang; John G Geisler; Ping Wang; Ioanna Petrounia; Selyna Mai; Charles Smith; Hossein Askari; Geoffrey T Struble; Robyn Williams; Sanjay Bhanot; Brett P Monia; Shariff Bayoumy; Eugene Grant; Gary W Caldwell; Matthew J Todd; Yin Liang; Micheal D Gaul; Keith T Demarest; Margery A Connelly
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Publication Detail:
Type:  Journal Article     Date:  2012-04-03
Journal Detail:
Title:  Journal of lipid research     Volume:  53     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-10     Completed Date:  2012-09-07     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1106-16     Citation Subset:  IM    
Affiliation:
Cardiovascular and Metabolic Disease Research and Community of Research Excellence and Advanced Technology, Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, PA 19477, USA. jqi@its.jnj.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Diacylglycerol O-Acyltransferase / antagonists & inhibitors,  genetics,  metabolism*
Enzyme Assays / methods*
Enzyme Inhibitors / pharmacology
Esterification / drug effects
Fatty Acids / biosynthesis,  metabolism
Glycerol / metabolism*
Hep G2 Cells
Humans
Isotope Labeling
Lipoproteins, VLDL / metabolism
Liver / enzymology*
Male
Mice
Oleic Acid / metabolism*
Oligonucleotides, Antisense / genetics
Triglycerides / biosynthesis
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Fatty Acids; 0/Lipoproteins, VLDL; 0/Oligonucleotides, Antisense; 0/Triglycerides; 112-80-1/Oleic Acid; 56-81-5/Glycerol; EC 2.3.1.20/DGAT1 protein, human; EC 2.3.1.20/DGAT2 protein, human; EC 2.3.1.20/Diacylglycerol O-Acyltransferase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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