Diglyceride acyltransferase


Diglyceride 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 and adipose tissue formation.
The protein is homologous to other membrane-bound O-acyltransferases.

Isoforms

There are two isozymes of DGAT encoded by the genes DGAT1 and DGAT2. Although both isozymes catalyze similar reactions, they have no sequence homology to each other.
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.
is mainly located in fat, liver and skin cells.

Mutations

In humans, DGAT1 mutations have been linked to congenital diarrheal disorders. The 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. 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 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, 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.
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.