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

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

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. DAGs can act as s ...

and

fatty acyl-CoA Fatty acyl-CoA esters are fatty acid derivatives formed of one fatty acid, a 3'-phospho-AMP linked to phosphorylated pantothenic acid (vitamin B5) and cysteamine. Long-chain acyl-CoA esters are substrates for a number of important enzymatic rea ...

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

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

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 membrane-bound O-acyltransferases.

Isoforms

Two 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. dif ...

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 conversion of ...

and DGAT2. Although both isozymes catalyze similar reactions, they share no sequence homology.
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 i ...

cells that line the intestine and duodenum where it reassembles

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

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 particle''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85 ...

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

. 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 Lactate may refer to: * Lactation, the secretion of milk from the mammary glands * Lactate, the conjugate base of lactic acid Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with w ...

, 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, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

and a number of DGAT-1 inhibitors are in

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

for this indication.

References

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