<i>DGAT1</i> promoter polymorphism associated with alterations in body mass index, high density lipoprotein levels and blood pressure in Turkish women

Ludwig, E H; Mahley, Robert W.; Palaoğlu, Erhan; Özbayrakci, Sinan; Balestra, Maureen E.; Borecki, Ingrid B.; Innerarity, Thomas L.; Farese, Robert V.

doi:10.1034/j.1399-0004.2002.620109.x

Cited by 50 publications

(31 citation statements)

References 14 publications

(14 reference statements)

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“…The DGAT T79C C allele is associated with increased promoter activity and higher BMI in Turkish women. 51 However, this has not been confirmed in a large French cohort. 52 Other genes involved in TAG storage such as lipoprotein lipase (LPL), acylation stimulating protein (ASP) and fatty acid binding proteins (FABPs) are not implicated in susceptibility to obesity.…”

Section: Pathways Controlling Lipid Storage In Adipocytesmentioning

confidence: 89%

Obesity and polymorphisms in genes regulating human adipose tissue

Dahlman

Arner

2007

Int J Obes

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Obesity is the result of an imbalance between food intake and energy expenditure resulting in the storing of energy as fat. Adipose tissue contains the largest store of energy in the body and plays important roles in regulating energy partitioning. Developments in genomics, in particular microarray-based expression profiling, have provided scientists with a number of new candidate genes whose expression in adipose tissue is regulated by obesity. Integrating expression profiles with genome-wide linkage and/or association analyses is a promising strategy to identify new genes underlying susceptibility to obesity. This article provides a comprehensive review of adipose-tissue-expressed genes implicated in predisposition to human obesity. The authors consider the following genes of particular interest: peroxisome proliferator-activated receptor gamma and, potentially, INSIG2 acting in adipogenesis; the adrenoreceptors beta 2 and 3, as well as hormone-sensitive lipase acting on lipolysis; uncoupling protein 2 acting in mitochondria energy expenditure; and among secreted molecules the cytokine tumor necrosis factor alpha and the hormone leptin. With the rapid development in genome research, we predict that additional alleles in genes regulating adipose tissue function will be established as risk factors for common obesity in the coming years. This has important implications for the prevention of obesity and may also offer new therapeutic targets.

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Section: Pathways Controlling Lipid Storage In Adipocytesmentioning

confidence: 89%

Obesity and polymorphisms in genes regulating human adipose tissue

Dahlman

Arner

2007

Int J Obes

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“…Thus, transcription of the MGAT2 gene may similarly be subject to transactivation by PPAR␣ or other isoforms of PPAR in response to elevated levels of fatty acids in the mucosa to increase the rate of dietary absorption. Future studies are also needed to depict a role of MGAT2 in human obesity, such as a possible linkage of MGAT2 polymorphism with certain types of human obesity as demonstrated with DGAT (47,48). Furthermore, generation and characterization of mice deficient in MGAT2 expression will shed important light on a role for MGAT2 in dietary fat absorption, as well as in diet-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

A Predominant Role of Acyl-CoA:monoacylglycerol Acyltransferase-2 in Dietary Fat Absorption Implicated by Tissue Distribution, Subcellular Localization, and Up-regulation by High Fat Diet

Cao

Hawkins

Brozinick

et al. 2004

Journal of Biological Chemistry

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Acyl-CoA:monoacylglycerol acyltransferase-2 (MGAT2) catalyzes the synthesis of diacylglycerol and differs from the MGAT1 and MGAT3 in tissue distribution at the mRNA level. In addition to the small intestine, MGAT2 mRNA is also expressed at high levels in human liver, the lower gastrointestinal tract, and the mouse kidney, but the physiological significance of such expression has not yet been studied. Using an affinitypurified antibody, the present study investigated the expression of murine MGAT2 protein along the intestinal tract, determined its subcellular localization, and studied its regulation by diet and in db/db mouse. Results demonstrate a high level of MGAT2 expression in the small intestine in a proximal-to-distal gradient that correlated well with both MGAT enzyme activity and fat absorption pattern. In contrast, MGAT2 protein was not detectable in other sections of the digestive tract, including stomach, cecum, colon, and rectum, or other mouse tissues such as kidney, liver, and adipocytes. Immunohistological studies provided direct evidence that the enzyme is expressed not only in the villi, but also in the crypt regions of the small intestine, which suggests that MGAT2 expression occurs prior to the maturation of enterocytes. MGAT2 is localized in the endoplasmic reticulum (ER) in both MGAT2-transfected COS-7 and Caco-2 cells, indicating that the ER is the primary site for dietary fat re-synthesis. MGAT2 expression appeared not to be affected by diabetes in the db/db mouse, however, the total intestinal MGAT activity was significantly enhanced. Finally, an up-regulation of both MGAT2 protein expression and MGAT activity was observed in mice fed a high fat diet, implicating a role of MGAT2 in diet-induced obesity. Taken together, our data suggest a predominant role of MGAT2 in dietary fat absorption.In mammals, the small intestine plays a predominant role in the absorption of dietary lipids (mainly triacylglycerol). The absorption of triacylglycerols by the intestinal tract is a complex process that requires several steps, including the hydrolysis of triacylglycerols by pancreatic lipase in the intestinal lumen, the uptake of released 2-monoacylglycerol and fatty acids into enterocytes, and the reconstitution of triacylglycerol in the enterocytes by the monoacylglycerol pathway where 2-monoacylglycerol and fatty acids are utilized to sequentially re-synthesize diacylglycerol and triacylglycerol by acyl-CoA: monoacylglycerol acyltransferase (MGAT) 1 and acyl-CoA:diacylglycerol acyltransferase (DGAT), respectively. Another pathway involved in the triacylglycerol synthesis is the glycerol 3-phosphate pathway, a de novo pathway that is present in most tissues, including small intestine. The pathway begins with acylation of glycerol 3-phosphate with fatty acyl-CoA producing lysophosphatidic acid, followed sequentially by further acylation and dephosphorylation to yield diacylglycerol (1). Both pathways share the final step converting diacylglycerol to triacylglycerol by DGAT. In the small intestinal muc...

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“…These findings indicate a robust upregulation of DGAT1 and DGAT2 during adipogenesis and suggest the involvement of C/EBPa or PPARg, transcription factors that control the expression of many genes in adipogenesis. A PPAR binding site occurs in the DGAT1 promoter (89), and thiazolidinediones, which activate PPARg, increase DGAT1 mRNA levels in adipocyte cell lines and adipose tissues of mice and humans (90). C/ EBPb and C/EBPa increase the expression of DGAT2 mRNA in adipogenesis (91).…”

Section: Regulation Of Dgat Enzymesmentioning

confidence: 99%

“…Several common sequence polymorphisms are present in the 5′ noncoding sequences of the DGAT1 gene (89). One of these polymorphisms, C79T, affects promoter activity in cultured cells and has been associated with alterations in body mass index, diastolic blood pressure, and HDL cholesterol levels in Turkish women (89).…”

Section: Dgat Enzymes In Humansmentioning

confidence: 99%

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Yen

Stone

Koliwad

et al. 2008

Journal of Lipid Research

912

782

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Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acylCoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases.-Yen, C-L. E., S. J. Stone, S. Koliwad, C. Harris, and R. V. Farese, Jr. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 2008. 49: 2283-2301. Supplementary key words triacylglycerolsTriacylglycerols (triglycerides) (TGs), a major type of neutral lipid, are a heterogeneous group of molecules with a glycerol backbone and three FAs attached by ester bonds. The physical and chemical properties of TG differ based on chain length and the degree to which their FAs are desaturated. TGs serve multiple important functions in living organisms. Chief among these, they are the major storage molecules of FA for energy utilization and the synthesis of membrane lipids. Because they are highly reduced and anhydrous, TGs store 6-fold more energy than the same amount of hydrated glycogen (1). In plants, TGs are a major component of seed oils, which are valuable resources for dietary consumption and industrial uses. TG from plants and microorganisms can also be used for biofuels. In animals, energy stores of TG are concentrated primarily in adipocytes, although TGs are also found prominently in myocytes, hepatocytes, enterocytes, and mammary epithelial cells. In addition to energy storage, TG synthesis in cells may protect them from the potentially toxic effects of excess FA. In the enterocytes and hepatocytes of most mammals, TGs are synthesized for the assembly and secretion of lipoproteins, which transport dietary and endogenously synthesized FA between tissues. Also, TGs in secreted lipids acts as a component of the skinʼs surface water barrier, and collections of TG in adipose tissue provide insulation for organisms.Although TGs are essential for normal physiology, the excessive accumulation of TG in human adipose tissue results in obesity and, in nonadipose tissues, is associated with organ dysfunction. For example, excessive TG deposition in skeletal muscle and the liver is associated with insulin resistance, in the liver with nonalcoholic steatohepatitis, and in the heart with cardiomyopathy (2, 3). Owing to worldwide increases in the p...

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DGAT1 promoter polymorphism associated with alterations in body mass index, high density lipoprotein levels and blood pressure in Turkish women

Cited by 50 publications

References 14 publications

Obesity and polymorphisms in genes regulating human adipose tissue

Obesity and polymorphisms in genes regulating human adipose tissue

A Predominant Role of Acyl-CoA:monoacylglycerol Acyltransferase-2 in Dietary Fat Absorption Implicated by Tissue Distribution, Subcellular Localization, and Up-regulation by High Fat Diet

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

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