Diglyceride acyltransferase (or ''O''-acyltransferase), DGAT, catalyzes the formation of

triglycerides A triglyceride (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and oth ...

(triacylglycerols) from

diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. Diglycerides are n ...

and

acyl-CoA Acyl-CoA is a group of coenzyme A, CoA-based coenzymes that metabolize carboxylic acids. Fatty acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several e ...

. The reaction catalyzed by DGAT is considered the terminal and only

committed step In biochemistry, the committed step (also known as the ''first'' committed step) is an effectively irreversible, enzyme- catalyzed reaction that occurs at a branch point during the biosynthesis of some molecules. As the name implies, after this ...

in the acyl-CoA-dependent triglyceride synthesis, universally important in animal, plants, and microorganisms. The conversion is essential for intestinal absorption (i.e. DGAT1) and adipose tissue formation (i.e. DGAT2) in mammalian. DGAT1 are homologous to other membrane-bound ''O''-acyltransferases, but not all other DGATs.

Isoforms

Two important DGAT

isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...

s are encoded by the genes

DGAT1 Diacylglycerol ''O''-acyltransferase 1 is an enzyme that in humans is encoded by the ''DGAT1'' gene. Function This gene encodes a multipass transmembrane protein that functions as a key metabolic enzyme. The encoded protein catalyzes the conver ...

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 Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase ...

cells that line the intestine and duodenum where it reassembles

triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...

s 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 Chylomicrons (from the Greek χυλός, chylos, meaning ''juice'' (of plants or animals), and micron, meaning ''small''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85–92%), ...

.
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 The University of California, San Francisco (UCSF) is a public land-grant research university in San Francisco, California, United States. It is part of the University of California system and is dedicated entirely to health science and life ...

. 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 Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

and a number of DGAT-1 inhibitors are in

clinical trials Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

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

References

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