Diglyceride acyltransferase explained

diacylglycerol O-acyltransferase
Ec Number:2.3.1.20
Cas Number:9029-98-5
Go Code:0004144
Hgncid:2843
Entrezgene:8694
Omim:604900
Refseq:NM_012079
Uniprot:O75907
Chromosome:8
Arm:q
Band:24.3

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.

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. The location of DGAT1 and DGAT2 in other organisms, as well as other DGATs have been reported in various literatures.

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.

Notes and References

  1. Chen . Guanqun . Harwood . John L. . Lemieux . M. Joanne . Stone . Scot J. . Weselake . Randall J. . November 2022 . Acyl-CoA:diacylglycerol acyltransferase: Properties, physiological roles, metabolic engineering and intentional control . [Progress in Lipid Research] . 88 . 101181 . 10.1016/j.plipres.2022.101181 . 35820474. free .
  2. 10.1194/jlr.R800018-JLR200 . free . Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. 2008. Yen. Chi-Liang Eric. Stone. Scot J.. Koliwad. Suneil. Harris. Charles. Farese. Robert V.. Journal of Lipid Research. 49. 11. 2283–2301. 18757836. 3837458.
  3. Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL . Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes . The Journal of Biological Chemistry . 273 . 41 . 26765–71 . October 1998 . 9756920 . 10.1074/jbc.273.41.26765 . free .
  4. Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV . Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members . The Journal of Biological Chemistry . 276 . 42 . 38870–6 . October 2001 . 11481335 . 10.1074/jbc.M106219200 . free .
  5. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, Farese RV . Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat . Nature Genetics . 25 . 1 . 87–90 . May 2000 . 10802663 . 10.1038/75651 . 10043699 .
  6. Stone SJ, Myers HM, Watkins SM, Brown BE, Feingold KR, Elias PM, Farese RV . Lipopenia and skin barrier abnormalities in DGAT2-deficient mice . The Journal of Biological Chemistry . 279 . 12 . 11767–76 . March 2004 . 14668353 . 10.1074/jbc.M311000200 . free .
  7. Chen HC, Farese RV . Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice . Arteriosclerosis, Thrombosis, and Vascular Biology . 25 . 3 . 482–6 . March 2005 . 15569818 . 10.1161/01.ATV.0000151874.81059.ad . free .
  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 . 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 . October 2008 . 18768481 . 2662058 . 10.1074/jbc.M800494200 . free .
  9. News: Pfizer, Bristol finalize deal on metabolic drugs . Reuters . 2007-08-27 . 2007-08-27.

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