Diglyceride acyltransferase

Isoforms

Two important DGAT isozymes are encoded by the genes DGAT1 and DGAT2. 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 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. In contrast, DGAT2−/− mice 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 and a number of DGAT-1 inhibitors are in clinical trials for this indication.

DGAT is also important in lipid biotechnology in plants, microorganisms, and animals.

References

References

1. (November 2022). "Acyl-CoA:diacylglycerol acyltransferase: Properties, physiological roles, metabolic engineering and intentional control". [[Progress in Lipid Research]].
2. (2008). "Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis". Journal of Lipid Research.
3. (October 1998). "Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes". The Journal of Biological Chemistry.
4. (October 2001). "Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members". The Journal of Biological Chemistry.
5. (May 2000). "Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat". Nature Genetics.
6. (March 2004). "Lipopenia and skin barrier abnormalities in DGAT2-deficient mice". The Journal of Biological Chemistry.
7. (March 2005). "Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice". Arteriosclerosis, Thrombosis, and Vascular Biology.
8. (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.
9. (2007-08-27). "Pfizer, Bristol finalize deal on metabolic drugs". Reuters.