Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis

Cases, Sylvaine; Smith, Steven J.; Zheng, Yao-Wu; Myers, Heather; Lear, Steven R.; Sande, Eric; Novak, Sabine; Collins, Colin C.; Welch, Carrie B.; Lusis, Aldons J.; Erickson, Sandra K.; Farese, Robert V.

doi:10.1073/pnas.95.22.13018

Cited by 986 publications

(849 citation statements)

References 32 publications

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“…DGAT-1 is considered as a microsomal enzyme (E.C. 2.3.1.20) able to catalyse the only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates (Cases et al 1998). Situated on BTA14, the DGAT1 gene encodes 489 amino acids and comprises 17 exons.…”

Section: Molecular Approachmentioning

confidence: 99%

Genetic variability of milk fatty acids

Arnould

Soyeurt

2009

J Appl Genet

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Section: Molecular Approachmentioning

confidence: 99%

Genetic variability of milk fatty acids

Arnould

Soyeurt

2009

J Appl Genet

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“…4 DGAT1 encodes a diacyl CoA:diacylglycerol acyl transferase (DGAT) that converts diacylglycerides to triglycerides (TGs) by adding an acyl CoA moiety. 5 The enzyme belongs to the family of membrane-bound O-acyl transferases (MBOATs), with its active domain located in the lumenal region of the endoplasmic reticulum (ER). In the small intestine, DGAT helps to absorb TGs, whereas in the liver it produces TGs from fatty acids synthesized de novo or taken up from the circulation.…”

Section: Introductionmentioning

confidence: 99%

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

et al. 2016

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Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

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“…For example, it has been previously shown in genetically modified mouse models with inhibition of FA storage in WAT there is upregulation of FA oxidation in skeletal muscle, demonstrating the interplay of energy fluxes between the two organs. One such model is the diacylglycerol acyltransferase (DGAT) knockout mice (DGAT is the enzyme that catalyses the final acylation step of triacylglyceride synthesis 4 ). This shows reduced fat deposition and resistance to diet-induced obesity, due to the disruption in FA storage.…”

Section: Introductionmentioning

confidence: 99%

Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

2004

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Obesity and type 2 diabetes mellitus are the major noncommunicable public health problem of the 21st century. The best strategy to tackle this problem is to develop strategies to prevent/treat obesity. However, it is becoming clear that despite successful research identifying weight regulatory pathways, the development of the obesity epidemic is outpacing scientific progress. The lack of success controlling the obesity epidemic in an aging population will result in another subsequent uncontrolled epidemic of complications. Our research focuses on the mechanisms causing lipotoxicity aiming to identify suitable strategies to prevent or at least retard the development of the metabolic syndrome. Previous work using transgenic and knockout mouse models has shown an interplay between white adipose tissue and skeletal muscle linking fatty acid (FA) synthesis with reciprocal effects on FA oxidation. Work from our lab and others suggests that defective adipose tissue is a key link between obesity, insulin resistance and type 2 diabetes mellitus by promoting the development of lipotoxicity in peripheral tissues. We propose a series of models to describe the process by which the adipose tissue could react to an energy-rich environment and responds depending on genetic and physiological factors, impacting on the functions of other peripheral tissues. We suggest that by examining hypotheses that encompass multiple organs and the partitioning of energy between these organs, a suitable strategy can be devised for the treatment of chronic obesity.

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Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis

Cited by 986 publications

References 32 publications

Genetic variability of milk fatty acids

Genetic variability of milk fatty acids

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation

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