HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 44, 29802-29811, October 31, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/44/29802    most recent M800494200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cheng, D. Articles by Hussain, M. M. Search for Related Content PubMed PubMed Citation Articles by Cheng, D. Articles by Hussain, M. M. Social Bookmarking                      What's this?

Acylation of Acylglycerols by Acyl Coenzyme A:Diacylglycerol Acyltransferase 1 (DGAT1)

FUNCTIONAL IMPORTANCE OF DGAT1 IN THE INTESTINAL FAT ABSORPTION^*

Dong Cheng¹, 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, and M. Mahmood Hussain

From the Departments of Metabolic Diseases, ^¶Leads Evaluation, and ^||Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-5400 and the Departments of Anatomy and Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York 11203

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 µM), the major acylation product by DGAT1 was TAG; however, increased concentrations of 2-MAG (50–200 µM) 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 (IC₅₀ of human DGAT1: 16.6 ± 4.0 nM (MAG as substrate) and 1499 ± 318 nM (DAG as substrate); IC₅₀ values of human DGAT2, MGAT2, and MGAT3 are >30,000 nM). Using this pharmacological tool, we have shown that 76 and 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 50%. Based on these data, we conclude that the acylation of acylglycerols by DGAT1 is important for dietary fat absorption in the intestine.

Received for publication, January 18, 2008 , and in revised form, August 13, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400. Tel.: 609-818-5480; Fax: 609-818-3600; E-mail: dong.cheng{at}bms.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Shi and D. Cheng Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism Am J Physiol Endocrinol Metab, July 1, 2009; 297(1): E10 - E18. [Abstract] [Full Text] [PDF]