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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 the formation of adipose tissue.[1]
The protein is homologous to other membrane-bound O-acyltransferases.
Isoforms
There are two isozymes of DGAT encoded by the genes DGAT1[2] and DGAT2.[3] Although both isozymes catalyze similar reactions, they have no sequence homology to each other.
Knockout studies
Mice with genetic disruption of the dgat1 or dgat2 genes have been made by the Farese laboratory at UCSF. Surprisingly, DGAT1−/− mice[4] 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. In contrast, DGAT2−/− mice[5] 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
DGAT-1 inhibitors have potential for the treatment of obesity[6][7] and a number of DGAT-1 inhibitors are in clinical trials for this indication.[8]
^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. PMID9756920.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^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. PMID11481335.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^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. PMID10802663.
^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. PMID14668353.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^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. PMID15569818.
