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.
Contents
1Isoforms
2Mutations
3Knockout studies
4Therapeutic application
5References
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
^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.
^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.
^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.
^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.
^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.
^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.
^ 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.
^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.
…acid diarrhea , chylomicron retention disease (also known as Anderson disease []), and diacylglycerolacyltransferase 1 deficiency These disorders are discussed separately. Neuroendocrine tumors affecting…
…have low serum albumin and IgG as well. Causes include a protein-losing enteropathy (eg, diacylglycerolacyltransferase 1 [DGAT1] deficiency, complement decay-accelerating factor [CD55] deficiency, or lymphangiectasia)…
…nucleotide-releasing protein (RasGRP) is also recruited to the plasma membrane upon generation of diacylglycerol (DAG) and activated by protein kinase C (PKC)-theta-mediated serine phosphorylation. SLP-76 is also …
…THBD – Encodes thrombomodulin, which also has roles in the coagulation cascade; DGKE – Encodes diacylglycerol kinase epsilon, which also appears to have a role in some forms of nephrotic syndrome; The CFH-CFHR…
…PLC can cause the hydrolysis of phosphatidylinositol 4,5 bisphosphate (PIP2) to 1,2 diacylglycerol and IP3. Diacylglycerol and IP3 can then act as regulators of cell metabolism. This pathway can alter cell …
English Journal
Identification and function analysis of a type 2 diacylglycerol acyltransferase (DGAT2) from the endosperm of coconut (Cocos nucifera L.).
Zheng Y, Jin Y, Yuan Y, Feng D, Chen L, Li D, Zhou P.
Gene. 2019 Jun;702()75-82.
Coconut (Cocos nucifera L.) is one of the most characteristic plants of tropical areas. Coconut oil and its derivatives have been widely used in various industries. In this paper, a type 2 diacylglycerol acyltransferase (DGAT2), which is one of the key enzymes involved in triacylglycerol (TAG) biosy
Accelerating the discovery of DGAT1 inhibitors through the application of parallel medicinal chemistry (PMC).
Yu Y, Wu Z, Shi ZC, He S, Lai Z, Cernak TA, Vachal P, Liu M, Liu J, Hong Q, Jian T, Guiadeen D, Krikorian A, Sperbeck DM, Verras A, Sonatore LM, Murphy BA, Wiltsie J, Chung CC, Gorski JN, Liu J, Xiao J, Wolff M, Tong SX, Madeira M, Karanam BV, Shen DM, Balkovec JM, De Vita RJ, Pinto S, Nargund RP.
The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to
RNA-seq data reveals a coordinated regulation mechanism of multigenes involved in the high accumulation of palmitoleic acid and oil in sea buckthorn berry pulp.
Ding J, Ruan C, Du W, Guan Y.
BMC plant biology. 2019 May;19(1)207.
Sea buckthorn is a woody oil crop in which palmitoleic acid (C16:1n7, an omega-7 fatty acid (FA)) contributes approximately 40% of the total FA content in berry pulp (non-seed tissue). However, the molecular mechanisms contributing to the high accumulation of C16:1n7 in developing sea buckthorn berr
… The mRNA levels of adipose triglyceride lipase (ATGL) and pyruvate dehydrogenase kinase 4 (PDK4) in abdominal WAT significantly increased by fasting, whereas the mRNA levels of diacylglycerolO-acyltransferase homolog 2 (DGAT2) and peroxisome proliferator-activated receptor-<i>γ</i> …
Effect of 50 Hz electric field in diacylglycerolacyltransferase mRNA expression level and plasma concentration of triacylglycerol, free fatty acid, phospholipid and total cholesterol.
… Background: The effects of exposure to a 50 Hz electric field (EF) on plasma level of triacylglycerol, free fatty acids, total cholesterol and phospholipid and mRNA expression level of diacylglycerolacyltransferase (DGAT) 1 and 2 in liver and intestines from C57BL/6 J mice were studied.Methods: The test was based on comparison between mice post treated with 50 Hz EF of 45 kV/m intensity for 30 min per day for 11 days or without EF. …
This gene encodes an multipass transmembrane protein that functions as a key metabolic enzyme. The encoded protein catalyzes the conversion of diacylglycerol and fatty acyl CoA to triacylglycerol. This enzyme can ...
This gene encodes one of two enzymes which catalyzes the final reaction in the synthesis of triglycerides in which diacylglycerol is covalently bound to long chain fatty acyl-CoAs. The encoded protein catalyzes this ...
Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. In contrast to DGAT2 it is not essential for survival. May be involved in VLDL (very low density ...