Validation of Diacyl Glycerolacyltransferase I as a Novel Target for the Treatment of Obesity and Dyslipidemia Using a Potent and Selective Small Molecule Inhibitor

Zhao, Gang; Souers, Andrew J.; Voorbach, Martin J.; Falls, Hugh D.; Droz, Brian A.; Brodjian, Sevan; Lau, Yau Yi; Iyengar, Rajesh; Gao, Ju; Judd, Andrew S.; Wagaw, Seble; Ravn, Matthew M.; Engstrom, Kenneth M.; Lynch, John K.; Mulhern, Mathew M.; Freeman, Jennifer C.; Dayton, Brian D.; Wang, Xiaojun; Grihalde, Nelson; Fry, Dennis G.; Beno, David W. A.; Marsh, Kennan C.; Su, Zhi; Diaz, Gilbert; Collins, Christine A.; Sham, Hing L.; Reilly, Regina M.; Brune, Michael E.; Kym, Philip R.

doi:10.1021/jm7013887

Cited by 135 publications

(111 citation statements)

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“…Thus, although the precise kinetics of chylomicron secretion in Dgat1 2/2 mice has not been studied, a dietary fat bolus probably empties into the circulation of these mice at a decreased but more sustained rate. This finding was reproduced in mice treated orally with a selective DGAT1 inhibitor (115)…”

Section: Dgat Enzymes and Lipoprotein Metabolismmentioning

confidence: 76%

“…Dgat1 2/2 mice have slower gastric emptying (unpublished observations), lower chylomicronemia after food intake, and more TG in enterocytes when fed a chronic high-fat diet, suggesting a role for DGAT1 in accelerating assimilation of TG from the diet (114). This conjecture is supported by recent studies of a potent and specific small-molecule inhibitor of DGAT1 that, when orally administered to mice, decreased the rate at which an oral fat bolus appeared as TG in the serum and also reduced weight gain in response to a high-fat diet (115). Increased energy expenditure in Dgat1 2/2 mice is multi- factorial, with male mice exhibiting increases in physical activity (34) and thermogenesis (97,113) The increased thermogenesis is probably owing in part to increased expression of uncoupling protein 1, a major mediator of nonshivering thermogenesis, in brown adipose tissue (97,113).…”

Section: Functions Of Dgat1 and Dgat2 In Energy Metabolismmentioning

confidence: 84%

“…Numerous agents have been reported to inhibit DGAT activity, including a variety of substances isolated from microorganisms (152)(153)(154)(155)(156) and fish oils (157), but it is unclear whether these agents inhibit one or both DGAT enzymes. Recently, a selective smallmolecule inhibitor of DGAT1 was reported to reduce weight gain and hepatic TG when administered to mice fed a high-fat diet (115). These findings indicate that pharmacologic inhibition of DGAT1 may have metabolic effects similar to those seen with inactivation of its gene in mice, raising the promise of DGAT1 inhibitors for the treatment of obesity, hepatic steatosis, and possibly diabetes mellitus.…”

Section: Dgat Inhibitorsmentioning

confidence: 98%

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Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Yen

Stone

Koliwad

et al. 2008

Journal of Lipid Research

908

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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Section: Dgat Enzymes and Lipoprotein Metabolismmentioning

confidence: 76%

Section: Functions Of Dgat1 and Dgat2 In Energy Metabolismmentioning

confidence: 84%

Section: Dgat Inhibitorsmentioning

confidence: 98%

See 1 more Smart Citation

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Yen

Stone

Koliwad

et al. 2008

Journal of Lipid Research

908

782

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“…3A). To test whether DGAT1 activity is required for the association of NS5A with LDs, we treated HCV-infected hepatoma cells with two structurally unrelated DGAT1 inhibitors (iA and iB) (11,16,21) and examined NS5A localization to LDs. At concentrations that inhibited cellular DGAT1 activity and HCV production (iA and iB: 20 and 75 M, respectively) (Fig.…”

Section: Ns5amentioning

confidence: 99%

Diacylglycerol Acyltransferase-1 Localizes Hepatitis C Virus NS5A Protein to Lipid Droplets and Enhances NS5A Interaction with the Viral Capsid Core

Camus

Herker

Modi

et al. 2013

Journal of Biological Chemistry

118

108

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Background:The NS5A protein regulates HCV assembly by localizing to lipid droplets. Results: The triglyceride-synthesizing enzyme DGAT1 binds NS5A, enhances interactions of NS5A with the viral capsid core, and enables lipid droplet localization of NS5A. Conclusion: DGAT1 functions as a cellular "hub" for HCV proteins to access lipid droplets. Significance: DGAT1 inhibitors suppress HCV assembly by preventing NS5A access to DGAT1-generated lipid droplets.

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“…The IC 50 of human recombinant DGAT1 is 0.019 ± 0.004 M; the IC 50 of human recombinant DGAT2, dog MTP, human recombinant ACAT2, human recombinant stearoyl-CoA desaturase 1 (SCD-1), the cellular apo B secretion assay, the human recombinant peroxisome proliferator-activated receptor ␣ (PPAR ␣ ) and PPAR ␥ , were all greater than 10 M ( Table 1 ). In addition, Abbott Laboratories has reported a highly potent and selective DGAT1 inhibitor, A-922500 ( 16 ), that has an IC 50 of 0.007 M when tested against human recombinant DGAT1 dependent LC/MS/MS response. The MS signal of triolein relative to the internal standard [1,3-di-heptadecanoyl-2-(10Z-heptadecanoyl)-sn -glycerol-d5] showed a linear response to approximately 1,600,000 MS units or approximately 1 M triolein.…”

Section: Metabolic Stable Isotope Labeling Of Vldl-tg In Ratsmentioning

confidence: 99%

High-content assays for evaluating cellular and hepatic diacylglycerol acyltransferase activity

Lang

Giardino

et al. 2010

Journal of Lipid Research

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that they are a major source of energy. TGs are synthesized from glycerol and three FA molecules; each FA is attached via an ester bond to hydroxyl groups of the glycerol backbone. Like many neutral lipids, TGs contain FA molecules with varying chain lengths; the most common are 16, 18, or 20 carbons. The two major biosynthetic pathways of TG are the glycerol-3-phosphate pathway, which exists primarily in liver and adipose tissues, and the monoacylglycerol pathway, which exists predominately in the intestine. The fi nal step of the glycerol-3-phosphate biosynthetic pathway can be catalyzed by either diacylglycerol acyltransferase 1 (DGAT1) or DGAT2 ( 1, 2 ). Although DGAT1 and DGAT2 both convert diacylglycerol (DAG) to TG, they do not share similarity in either their nucleotide or amino acid sequences.It has been reported that knockout mice lacking DGAT1 (DGAT1 Ϫ / Ϫ ) do not display obvious changes in TG metabolism in the liver ( 3 ). In contrast, knockout mice lacking DGAT2 (DGAT2 Ϫ / Ϫ ) display severely reduced TG content in the liver ( 4 ). Furthermore, studies have shown that suppression of DGAT2 with antisense oligonucleotides reduced hepatic TG content in rodents ( 5, 6 ) producing reversed diet-induced hepatic steatosis and insulin resistance in rats ( 5 ). These results suggest that DGAT1 and DGAT2 function differently in TG biosynthesis. The fi nding that multiple enzymes catalyze the synthesis of TG from DAG presents an opportunity to modulate one catalytic mechanism of this biochemical reaction. This type of modulation may produce therapeutic results without the potential adverse side effects that might occur if TG synthesis were completely inhibited in all tissues. By specifically inhibiting the activity of DGAT1 or DGAT2, compounds that inhibit the conversion of DAG to TG will be useful in lowering absorption and circulating concentrations of TG.Abstract Acyl -CoA:diacylglycerol acyltransferase (DGAT) catalyzes the terminal step in triglyceride (TG) synthesis using diacylglycerol (DAG) and fatty acyl-CoA as substrates. In the liver, the production of VLDL permits the delivery of hydrophobic TG from the liver to peripheral tissues for energy metabolism. We describe here a novel high-content, high-throughput LC/MS/MS-based cellular assay for determining DGAT activity. We treated endogenous DGATexpressing cells with stable isotope-labeled [

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Validation of Diacyl Glycerolacyltransferase I as a Novel Target for the Treatment of Obesity and Dyslipidemia Using a Potent and Selective Small Molecule Inhibitor

Cited by 135 publications

References 12 publications

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Diacylglycerol Acyltransferase-1 Localizes Hepatitis C Virus NS5A Protein to Lipid Droplets and Enhances NS5A Interaction with the Viral Capsid Core

High-content assays for evaluating cellular and hepatic diacylglycerol acyltransferase activity

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