Diglyceride acyltransferase

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diacylglycerol O-acyltransferase
Identifiers
EC number2.3.1.20
CAS number9029-98-5
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
diacylglycerol O-acyltransferase 1
Identifiers
SymbolDGAT1
Entrez8694
HUGO2843
OMIM604900
RefSeqNM_012079
UniProtO75907
Other data
LocusChr. 8 q24.3
diacylglycerol O-acyltransferase 2
Identifiers
SymbolDGAT2
Entrez84649
HUGO16940
OMIM606983
RefSeqNM_032564
UniProtQ96PD7
Other data
LocusChr. 11 q13.3

Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides from diacylglycerol and Acyl-CoA. The reaction catalyzed by DGAT is considered the terminal and only committed step in triglyceride synthesis and to be essential for intestinal absorption (i.e. DGAT1) [1] and adipose tissue formation (i.e. DGAT2).[2]

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

Isoforms

There are two isozymes of DGAT encoded by the genes DGAT1[3] and DGAT2.[4] Although both isozymes catalyze similar reactions, they have no sequence homology to each other.

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.

Mutations

In humans, DGAT1 mutations have been linked to congenital diarrheal disorders [5][6][7]. The congenital diarrheal disorder presents 2-3 days after birth with projectile vomiting and failure to thrive. The congenital diarrheal disorder may be treated with total parenteral nutrition avoiding sepsis with most symptoms resolving at 10 to 12 months of age. The congenital diarrheal disorder requires a strict diet with little or no fat (i.e fatty acids, monoglycerides, diglycerides, and triglycerides which break down and combine to form DGAT1 substrates that build up and irritate the intestinal mucosa). The precise cause of diarrhea is unknown, and is speculated to relate to abnormal fat absorption and buildup of DGAT1 substrates in the intestinal mucosa.

Knockout studies

Mice with genetic disruption of the DGAT1 or DGAT2 genes have been made by the Farese laboratory at UCSF. Surprisingly, DGAT1−/− mice[8] 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.[8] In contrast, DGAT2−/− mice[9] 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[10][11] and a number of DGAT-1 inhibitors are in clinical trials for this indication.[12] However, recent findings prompt concern for DGAT1 inhibition in humans because of the severe side effects which include nausea, diarrhea, and vomiting following meals containing fat [13]. However it is important to note that these symptoms were observed in case of total loss of function in DGAT due to knockout mutation. Such symptoms are not observed in case of partial inhibition of DGAT activity such as those induced via medication.

References

  1. ↑ Haas, JT; Winter, HS; Lim, E; Kirby, A; Blumenstiel, B; DeFelice, M; Gabriel, S; Jalas, C; Branski, D; Grueter, CA; Toporovski, MS; Walther, TC; Daly, MJ; Farese RV, Jr (December 2012). "DGAT1 mutation is linked to a congenital diarrheal disorder". The Journal of Clinical Investigation. 122 (12): 4680–4. doi:10.1172/JCI64873. PMC 3533555. PMID 23114594.
  2. ↑ Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, Novak S, Collins C, Welch CB, Lusis AJ, Erickson SK, Farese RV (October 1998). "Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis". Proceedings of the National Academy of Sciences of the United States of America. 95 (22): 13018–23. doi:10.1073/pnas.95.22.13018. PMC 23692. PMID 9789033.
  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. ↑ Haas, JT; Winter, HS; Lim, E; Kirby, A; Blumenstiel, B; DeFelice, M; Gabriel, S; Jalas, C; Branski, D; Grueter, CA; Toporovski, MS; Walther, TC; Daly, MJ; Farese RV, Jr (December 2012). "DGAT1 mutation is linked to a congenital diarrheal disorder". The Journal of Clinical Investigation. 122 (12): 4680–4. doi:10.1172/JCI64873. PMC 3533555. PMID 23114594.
  6. ↑ Gluchowski, NL; Chitraju, C; Picoraro, JA; Mejhert, N; Pinto, S; Xin, W; Kamin, DS; Winter, HS; Chung, WK; Walther, TC; Farese RV, Jr (June 2017). "Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea". Journal of Lipid Research. 58 (6): 1230–1237. doi:10.1194/jlr.P075119. PMC 5454518. PMID 28373485.
  7. ↑ Stephen, J; Vilboux, T; Haberman, Y; Pri-Chen, H; Pode-Shakked, B; Mazaheri, S; Marek-Yagel, D; Barel, O; Di Segni, A; Eyal, E; Hout-Siloni, G; Lahad, A; Shalem, T; Rechavi, G; Malicdan, MC; Weiss, B; Gahl, WA; Anikster, Y (August 2016). "Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations". European Journal of Human Genetics. 24 (9): 1268–73. doi:10.1038/ejhg.2016.5. PMC 4989215. PMID 26883093.
  8. ↑ 8.0 8.1 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ "Pfizer, Bristol finalize deal on metabolic drugs". Reuters. 2007-08-27. Retrieved 2007-08-27.
  13. ↑ Haas, JT; Winter, HS; Lim, E; Kirby, A; Blumenstiel, B; DeFelice, M; Gabriel, S; Jalas, C; Branski, D; Grueter, CA; Toporovski, MS; Walther, TC; Daly, MJ; Farese RV, Jr (December 2012). "DGAT1 mutation is linked to a congenital diarrheal disorder". The Journal of Clinical Investigation. 122 (12): 4680–4. doi:10.1172/JCI64873. PMC 3533555. PMID 23114594.
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