Diglyceride acyltransferase

In this article, we will explore Diglyceride acyltransferase in depth and its impact on our daily lives. From its origin to its contemporary relevance, we will analyze how Diglyceride acyltransferase has evolved over time and how it has affected different aspects of society. We will also examine the different perspectives and opinions related to Diglyceride acyltransferase, as well as its role in the current context. Through this comprehensive analysis, we hope to provide a complete and rich insight into Diglyceride acyltransferase, providing the reader with a deeper understanding of this topic.

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

Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides (triacylglycerols) from diacylglycerol and acyl-CoA.[1] The reaction catalyzed by DGAT is considered the terminal and only committed step in the acyl-CoA-dependent triglyceride synthesis, universally important in animal, plants, and microorganisms. The conversion is essential for intestinal absorption (i.e. DGAT1) and adipose tissue formation (i.e. DGAT2) in mammalian.[2] DGAT1 are homologous to other membrane-bound O-acyltransferases, but not all other DGATs.[1]

Isoforms

Two important DGAT isozymes are encoded by the genes DGAT1[3] and DGAT2.[4] Although both isozymes catalyze similar reactions, they share no sequence homology, which is similar to other DGATs reported in various organisms.[1] The location of DGAT1 and DGAT2 in other organisms, as well as other DGATs have been reported in various literatures.[1]

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 in mice

Mice with genetic disruption of the DGAT1 or DGAT2 genes have been made by the Farese laboratory at UCSF. Surprisingly, DGAT1−/− mice[5] 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.[5] In contrast, DGAT2−/− mice[6] 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[7][8] and a number of DGAT-1 inhibitors are in clinical trials for this indication.[9]

DGAT is also important in lipid biotechnology in plants, microorganisms, and animals.[1]

References

  1. ^ a b c d e Chen G, Harwood JL, Lemieux MJ, Stone SJ, Weselake RJ (November 2022). "Acyl-CoA:diacylglycerol acyltransferase: Properties, physiological roles, metabolic engineering and intentional control". Progress in Lipid Research. 88: 101181. doi:10.1016/j.plipres.2022.101181. PMID 35820474.
  2. ^ Yen CL, Stone SJ, Koliwad S, Harris C, Farese RV (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.
  3. ^ 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.
  4. ^ 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.
  5. ^ a b 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ "Pfizer, Bristol finalize deal on metabolic drugs". Reuters. 2007-08-27. Retrieved 2007-08-27.