DGAT1

Official Full Name

diacylglycerol O-acyltransferase 1

Organism

Homo sapiens

GeneID

8694

Background

This gene encodes an multipass transmembrane protein that functions as a key metabolic enzyme. The encoded protein catalyzes the conversion of diacylglycerol and fatty acyl CoA to triacylglycerol. This enzyme can also transfer acyl CoA to retinol. Activity of this protein may be associated with obesity and other metabolic diseases. [provided by RefSeq, Jul 2013]

Synonyms

ARAT; DGAT; ARGP1; DIAR7;

Bio Chemical Class

Acyltransferase

Protein Sequence

MGDRGSSRRRRTGSRPSSHGGGGPAAAEEEVRDAAAGPDVGAAGDAPAPAPNKDGDAGVGSGHWELRCHRLQDSLFSSDSGFSNYRGILNWCVVMLILSNARLFLENLIKYGILVDPIQVVSLFLKDPYSWPAPCLVIAANVFAVAAFQVEKRLAVGALTEQAGLLLHVANLATILCFPAAVVLLVESITPVGSLLALMAHTILFLKLFSYRDVNSWCRRARAKAASAGKKASSAAAPHTVSYPDNLTYRDLYYFLFAPTLCYELNFPRSPRIRKRFLLRRILEMLFFTQLQVGLIQQWMVPTIQNSMKPFKDMDYSRIIERLLKLAVPNHLIWLIFFYWLFHSCLNAVAELMQFGDREFYRDWWNSESVTYFWQNWNIPVHKWCIRHFYKPMLRRGSSKWMARTGVFLASAFFHEYLVSVPLRMFRLWAFTGMMAQIPLAWFVGRFFQGNYGNAAVWLSLIIGQPIAVLMYVHDYYVLNYEAPAAEA

Open

Disease

Acute diabete complication, Hepatitis virus infection, Hyper-lipoproteinaemia, Obesity, Type 2 diabetes mellitus

Approved Drug

1 +

Clinical Trial Drug

3 +

Discontinued Drug

3 +

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Detailed Information

Diacylglycerol O-acyltransferase-1 (DGAT1) synthesises triacylglycerols, which are essential for dietary fat absorption and fat storage in humans. DGAT1 belongs to the membrane-bound O-acyltransferase superfamily. DGAT1 belongs to the membrane-bound O-acyltransferase (MBOAT) superfamily. acylation process of lipids and proteins. It remains unclear how human DGAT1 (hDGAT1) or other MBOATs in mammals MBOAT family members in mammals recognise substrates and catalyse reactions.

Structure and Expression of DGAT1

Structure of the DGAT1 complex with the substrate oleoyl coenzyme A. Structure of the coenzyme A complex. Each DGAT1 protomer has nine transmembrane helices and eight Each DGAT1 protomer has nine transmembrane helices, eight of which form a conserved structural fold, which we define as the MBOAT fold. DGAT1's MBOAT folded structure opens up a hollow chamber in the membrane that encloses the highly conserved catalytic reaction. enclosing highly conserved catalytic residues. This chamber has two separate entrances that house two substrates DGAT1 can exist in homodimeric or homotetrameric forms. Both forms have similar enzymatic activity. DGAT1's N-terminus interacts with neighbouring protomers, and these interactions are necessary for the generation of enzymatic activity.

DGAT1 is highly expressed in the intestine to promote fatty acid absorption, and it is also expressed in the testis, adipose tissue, and liver. DGAT2 is highly expressed in the liver and adipose tissue, but less so in the intestine. However, there are few studies on the expression patterns and functions of DGAT1 and DGAT2 in human cancers.

Glioma and DGAT1:

Diacylglycerol kinases (DGKs) are a family of enzymes that catalyse the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). DGKs reduce DAG levels in cell membranes, limiting the function of DAG as a secondary messenger and as a precursor for phospholipid and TGs biosynthesis. In the brain, most DGKs are abundantly expressed and have subtype-specific regional distributions. Of the 10 known DGK isozymes, diacylglycerol kinase B (DGKB) is predominantly expressed in the cerebral cortex, whereas gliomas are expressed in the cerebral cortex. In contrast, gliomas are mainly located in the cerebral cortex. However, the function of DGKB in gliomas has been little studied. Diacylglycerol Acyltransferase 1 (DGAT1), catalyzes the esterification of acyl-coenzyme A (acyl-CoA).DGAT1 catalyzes the esterification of acyl-CoA (CoA) with diacylglycerol (DAG) to form TGs, up-regulated to reduce FA oxidation and protect against mitochondrial lipotoxicity. Mitochondrial lipotoxicity is prevented by storing excess FA in TGs. Since DGKB regulates the levels of DAG, a substrate of TG, it may also play an important role in gliomas. levels of DAG, a substrate of TG, it may also play an important role in the maintenance of lipid homeostasis, thereby regulating the growth of gliomas.

Figure 1. Chemical modelling illustrates the function of DGAT1 in the regulation of lipid homeostasis and the inhibition of the cytotoxic effects produced by DGAT1 on GBM cells.

DGAT1 and Intestinal Diseases

Patients deficient in DGAT1 have severe clinical features such as protein-losing enteropathy (PLE), vomiting and/or diarrhoea, fat intolerance and failure to grow and develop due to impaired fat metabolism but do well on a fat-restricted diet.The combination of PLE with diarrhoea may be the result of intestinal mucosal damage, and concomitant fat intolerance suggests that DGAT1 protects the epithelial cells from lipid-induced injury. Using dermal fibroblasts and intestinal organ tissues derived from patients, researchers found that DGAT1 mediates LD formation and that DGAT1 deficiency increases susceptibility to lipid-induced toxicity and apoptosis. However, LD formation in patient-derived DGAT1-deficient cells was not completely abolished by stimulation with the most common UFA, oleic acid (OA). To date, it has not been clarified how LD is formed in the absence of DGAT1 or by what mechanism LD protects epithelial cells from lipotoxicity.

References:

Cheng X, Geng F, Pan M, et al. Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress. Cell Metab. 2020;32(2):229-242.e8. doi:10.1016/j.cmet.2020.06.002
Wang L, Qian H, Nian Y, et al. Structure and mechanism of human diacylglycerol O-acyltransferase 1. Nature. 2020;581(7808):329-332. doi:10.1038/s41586-020-2280-2

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