Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides (triacylglycerols) from diacylglycerol and acyl-CoA (for a recent and comprehensive review about DGAT, see [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]
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 miceedit
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 applicationedit
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]
^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.
^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.
^ abSmith 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.
^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.
^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.
^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. PMC2662058. PMID 18768481.
diglyceride, acyltransferase, acyltransferase, dgat, catalyzes, formation, triglycerides, triacylglycerols, from, diacylglycerol, acyl, recent, comprehensive, review, about, dgat, reaction, catalyzed, dgat, considered, terminal, only, committed, step, acyl, de. Diglyceride acyltransferase or O acyltransferase DGAT catalyzes the formation of triglycerides triacylglycerols from diacylglycerol and acyl CoA for a recent and comprehensive review about DGAT see 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 diacylglycerol O acyltransferaseIdentifiersEC no 2 3 1 20CAS no 9029 98 5DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteinsdiacylglycerol O acyltransferase 1IdentifiersSymbolDGAT1NCBI gene8694HGNC2843OMIM604900RefSeqNM 012079UniProtO75907Other dataLocusChr 8 q24 3Search forStructuresSwiss modelDomainsInterPro Contents 1 Isoforms 2 Knockout studies in mice 3 Therapeutic application 4 ReferencesIsoforms editTwo 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 editMice 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 editDGAT1 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 edit 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 Yen CE 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 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 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 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 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 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 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 Pfizer Bristol finalize deal on metabolic drugs Reuters 2007 08 27 Retrieved 2007 08 27 Portal nbsp Biology Retrieved from https en wikipedia org w index php title Diglyceride acyltransferase amp oldid 1192461247, wikipedia, wiki, book, books, library,
