Diglyceride acyltransferase

Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides from diacylglycerol and fatty acyl-CoA. The reaction catalyzed by DGAT is considered the terminal and only committed step in triglyceride synthesis. The conversion is essential for intestinal absorption (i.e. DGAT1) and adipose tissue formation (i.e. DGAT2).[1]

diacylglycerol O-acyltransferase
Identifiers
EC no.2.3.1.20
CAS no.9029-98-5
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
diacylglycerol O-acyltransferase 1
Identifiers
SymbolDGAT1
NCBI gene8694
HGNC2843
OMIM604900
RefSeqNM_012079
UniProtO75907
Other data
LocusChr. 8 q24.3
Search for
StructuresSwiss-model
DomainsInterPro
diacylglycerol O-acyltransferase 2
Identifiers
SymbolDGAT2
NCBI gene84649
HGNC16940
OMIM606983
RefSeqNM_032564
UniProtQ96PD7
Other data
LocusChr. 11 q13.3
Search for
StructuresSwiss-model
DomainsInterPro

The protein is homologous to other membrane-bound O-acyltransferases.

Isoforms

Two DGAT isozymes are encoded by the genes DGAT1[2] and DGAT2.[3] Although both isozymes catalyze similar reactions, they share no sequence homology.

DGAT1 is mainly located in absorptive enterocyte cells that line the intestine and duodenum where it reassembles triglycerides that were decomposed through lipolysis in the process of intestinal absorption. DGAT1 reconstitutes triglycerides in a committed step after which they are packaged together with cholesterol and proteins to form chylomicrons.

DGAT2 is mainly located in fat, liver and skin cells.

Knockout studies

Mice with genetic disruption of the DGAT1 or DGAT2 genes have been made by the Farese laboratory at UCSF. Surprisingly, DGAT1−/− mice[4] are healthy and fertile and have no changes in triglyceride levels. These mice are also lean and resistant to diet-induced obesity, consequently generating interest in DGAT1 inhibitors for the treatment of obesity. However, these mice also fail to lactate, showing a complete lack of milk production due to their inability to produce milk lipid droplets.[4] In contrast, DGAT2−/− mice[5] have reduced triglyceride levels but are lipopenic, suffer from skin barrier abnormalities (including the inability to retain moisture), and die shortly after birth.

Therapeutic application

DGAT1 inhibitors have potential for the treatment of obesity[6][7] and a number of DGAT-1 inhibitors are in clinical trials for this indication.[8]

References
  1. Yen, Chi-Liang Eric; Stone, Scot J.; Koliwad, Suneil; Harris, Charles; Farese, Robert V. (2008). "Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis". Journal of Lipid Research. 49 (11): 2283–2301. doi:10.1194/jlr.R800018-JLR200. PMC 3837458. PMID 18757836.
  2. Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL (October 1998). "Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes". The Journal of Biological Chemistry. 273 (41): 26765–71. doi:10.1074/jbc.273.41.26765. PMID 9756920.
  3. Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV (October 2001). "Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members". The Journal of Biological Chemistry. 276 (42): 38870–6. doi:10.1074/jbc.M106219200. PMID 11481335.
  4. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, Farese RV (May 2000). "Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat". Nature Genetics. 25 (1): 87–90. doi:10.1038/75651. PMID 10802663. S2CID 10043699.
  5. Stone SJ, Myers HM, Watkins SM, Brown BE, Feingold KR, Elias PM, Farese RV (March 2004). "Lipopenia and skin barrier abnormalities in DGAT2-deficient mice". The Journal of Biological Chemistry. 279 (12): 11767–76. doi:10.1074/jbc.M311000200. PMID 14668353.
  6. Chen HC, Farese RV (March 2005). "Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (3): 482–6. doi:10.1161/01.ATV.0000151874.81059.ad. PMID 15569818.
  7. Cheng D, Iqbal J, Devenny J, Chu CH, Chen L, Dong J, Seethala R, Keim WJ, Azzara AV, Lawrence RM, Pelleymounter MA, Hussain MM (October 2008). "Acylation of acylglycerols by acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1). Functional importance of DGAT1 in the intestinal fat absorption". The Journal of Biological Chemistry. 283 (44): 29802–11. doi:10.1074/jbc.M800494200. PMC 2662058. PMID 18768481.
  8. "Pfizer, Bristol finalize deal on metabolic drugs". Reuters. 2007-08-27. Retrieved 2007-08-27.
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