Diglyceride acyltransferase (or O-acyltransferase), DGAT, catalyzes the formation of triglycerides from diacylglycerol and Acyl-CoA, fatty acyl-CoA]. The reaction catalyzed by DGAT is considered the terminal and only committed step in triglyceride synthesis. The conversion is essential for intestinal absorption (i.e. DGAT1) and adipose tissue formation (i.e. DGAT2). The protein is homologous to other MBOAT, membrane-bound O-acyltransferases.

Isoforms

Two DGAT isozymes are encoded by the genes DGAT1 and DGAT2. Although both isozymes catalyze similar reactions, they share no sequence homology.
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

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 lactation, 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.

References

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