| The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of diacylglycerol acyltransferase-1 and -2. | |
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MedLine Citation:
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PMID: 22493088 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. In order to dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with 13C3-D5-glycerol or 13C18-oleic acid, and profiled the major isotope-labeled TG species by LC/MS/MS. Selective DGAT1 and DGAT2 inhibitors demonstrated that 13C3-D5-glycerol incorporated TG synthesis was mediated by DGAT2, not DGAT1. Conversely, 13C18-oleoyl-incorporated TG synthesis was predominantly mediated by DGAT1. In order to trace hepatic TG synthesis and very low density lipoprotein triglyceride (VLDL-TG) secretion in vivo, we administered D5-glycerol to mice and measured plasma levels of D5-glycerol incorporated TG. Treatment with an antisense oligonucleotide (ASO) to DGAT2 led to a significant reduction in D5-glycerol incorporation into VLDL-TG. In contrast, the DGAT2 ASO had no effect on the incorporation of exogenously administered 13C18-oleic acid into VLDL-TG. Thus, our results indicate DGAT1 and DGAT2 mediate distinct hepatic functions: DGAT2 is primarily responsible for incorporating endogenously synthesized fatty acids into TG whereas, DGAT1 plays a greater role in esterifying exogenous fatty acids to glycerol. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-4-3 |
Journal Detail:
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Title: Journal of lipid research Volume: - ISSN: 0022-2275 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Johnson and Johnson Pharmaceutical Research and Development, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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