| Acylation of acylglycerols by acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1). Functional importance of DGAT1 in the intestinal fat absorption. | |
| | |
MedLine Citation:
|
PMID: 18768481 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of the four intestinal membrane bound acyltransferases implicated in dietary fat absorption. Recently, it was found that, in addition to acylating diacylglycerol (DAG), DGAT1 also possesses robust enzymatic activity for acylating monoacylglycerol (MAG) (Yen, C. L., Monetti, M., Burri, B. J., and Farese, R. V., Jr. (2005) J. Lipid Res. 46, 1502-1511). In the current paper, we have conducted a detailed characterization of this reaction in test tube, intact cell culture, and animal models. Enzymatically, we found that triacylglycerol (TAG) synthesis from MAG by DGAT1 does not behave according to classic Michaelis-Menten kinetics. At low concentrations of 2-MAG (<50 microm), the major acylation product by DGAT1 was TAG; however, increased concentrations of 2-MAG (50-200 microm) resulted in decreased TAG formation. This unique product/substrate relationship is similar to MGAT3 but distinct from DGAT2 and MGAT2. We have also found that XP620 is an inhibitor that selectively inhibits the acylation of MAG by DGAT1 (IC(50) of human DGAT1: 16.6+/-4.0 nM (MAG as substrate) and 1499+/-318 nM (DAG as substrate); IC(50) values of human DGAT2, MGAT2, and MGAT3 are >30,000 nM). Using this pharmacological tool, we have shown that approximately 76 and approximately 89% of the in vitro TAG synthesis initiated from MAG is mediated by DGAT1 in Caco-2 cell and rat intestinal mucosal membranes, respectively. When applied to intact cultured cells, XP620 substantially decreased but did not abolish apoB secretion in differentiated Caco-2 cells. It also decreased TAG and DAG syntheses in primary enterocytes. Last, when delivered orally to rats, XP620 decreased absorption of orally administered lipids by approximately 50%. Based on these data, we conclude that the acylation of acylglycerols by DGAT1 is important for dietary fat absorption in the intestine. |
| | |
Authors:
|
Dong Cheng; Jahangir Iqbal; James Devenny; Ching-Hsuen Chu; Luping Chen; Jessica Dong; Ramakrishna Seethala; William J Keim; Anthony V Azzara; R Michael Lawrence; Mary Ann Pelleymounter; M Mahmood Hussain |
Publication Detail:
|
Type: Journal Article Date: 2008-09-03 |
Journal Detail:
|
Title: The Journal of biological chemistry Volume: 283 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2008 Oct |
Date Detail:
|
Created Date: 2008-10-27 Completed Date: 2008-12-29 Revised Date: 2010-09-21 |
Medline Journal Info:
|
Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
|
Languages: eng Pagination: 29802-11 Citation Subset: IM |
Affiliation:
|
Department of Metabolic Diseases, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-5400, USA. dong.cheng@bms.com |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Administration, Oral Animals Caco-2 Cells Diacylglycerol O-Acyltransferase / biosynthesis*, physiology Dietary Fats Enterocytes / metabolism Fats / metabolism* Gene Expression Regulation* Heterocyclic Compounds, 1-Ring Humans Inhibitory Concentration 50 Intestinal Absorption / drug effects* Intestines / metabolism* Male Mice Rats Rats, Sprague-Dawley |
| Chemical | |
Reg. No./Substance:
|
0/Dietary Fats; 0/Fats; 0/Heterocyclic Compounds, 1-Ring; 0/XP 620; EC 2.3.1.20/DGAT1 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
Previous Document: Novel mechanism for suppression of hyperpolarization-activated cyclic nucleotide-gated pacemaker cha...
Next Document: Family-based samples can play an important role in genetic association studies.