Diacylglycerol acyltransferases: Potential roles as pharmacological targets

Pharmacology and Therapeutics

Volumn 118, Issue 3, 2008, Pages 295-302

  Zammit, Victor A ^a   Buckett, Linda K ^b   Turnbull, Andrew V ^b   Wure, Haja ^a   Proven, Andrew ^a  

^a UNIVERSITY OF WARWICK   (United Kingdom)

^b ASTRAZENECA   (United Kingdom)

Author keywords

Adipose tissue; Diacylglycerol acyltransferases; Lipoproteins; Liver; Secretion; Triglycerides

Indexed keywords

ACYLGLYCEROL PALMITOYLTRANSFERASE; CHYLOMICRON; DIACYLGLYCEROL ACYLTRANSFERASE; DIACYLGLYCEROL ACYLTRANSFERASE 1; DIACYLGLYCEROL ACYLTRANSFERASE 2; TRIACYLGLYCEROL; VERY LOW DENSITY LIPOPROTEIN;

ADIPOSE TISSUE; ADIPOSE TISSUE CELL; CATALYSIS; DIETARY INTAKE; DRUG TARGETING; ENZYME ACTIVITY; ENZYME DEFICIENCY; ENZYME INHIBITION; ENZYME MECHANISM; ENZYME REGULATION; ENZYME RELEASE; FATTY ACID METABOLISM; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; HUMAN; INSULIN RESISTANCE; INTESTINE CELL; LIPOGENESIS; LIPOLYSIS; LIVER CELL; MUSCLE TRAINING; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROCESSING; REVIEW;

ADIPOCYTES; ANIMALS; DIACYLGLYCEROL O-ACYLTRANSFERASE; DRUG DELIVERY SYSTEMS; GENE EXPRESSION; HUMANS; LIVER; OBESITY; TRIGLYCERIDES;

EID: 44649128516     PISSN: 01637258     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2008.03.010     Document Type: Review

References (71)

1. Abo-Hashema K.A., Cake M.H., Power G.W., and Clarke D. Evidence for triacylglycerol synthesis in the lumen of microsomes via a lipolysis-esterification pathway involving carnitine acyltransferases. J Biol Chem 274 (1999) 35577-35582
2. Alexander C.A., Hamilton R.L., and Havel R.J. Subcellular localization of B apoprotein of plasma lipoproteins in rat liver. J Cell Biol 69 (1976) 241-263
3. Bell R.M., Ballas L.M., and Coleman R.A. Lipid topogenesis. J Lipid Res 22 (1981) 391-403
4. Broadway N., Pease R., and Saggerson E. In: Quant P., and Eaton S. (Eds). Carnitine acyltransferases and associated transport processes in the endoplasmic reticulum: Missing links in the VLDL story?. Current Views of Fatty acid Oxidation and Ketogenesis: From Organelles to Point Mutations vol. 466 (1999), Luwer Academic/Plenum Publishers, New York 59-68
5. Buhman K.K., Smith S.J., Stone S.J., Repa J.J., Wong J.S., Knapp Jr. F.F., et al. DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis. J Biol Chem 277 (2002) 25474-25479
6. Cao J., Cheng L., and Shi Y. Catalytic properties of MGAT3, a putative triacylgycerol synthase. J Lipid Res 48 (2007) 583-591
7. Cartwright I.J., and Higgins J.A. Direct evidence for a two-step assembly of ApoB48-containing lipoproteins in the lumen of the smooth endoplasmic reticulum of rabbit enterocytes. J Biol Chem 276 (2001) 48048-48057
8. Cartwright I.J., and Higgins J.A. Direct evidence for a two step assembly of apo-B48 containing lipoproteins in the lumen of the smooth endoplasmic reticulum of rabbit enterocytes. J Biol Chem (2001) M104229200
9. Casaschi A., Maiyoh G.K., Adeli K., and Theriault A.G. Increased diacylglycerol acyltransferase activity is associated with triglyceride accumulation in tissues of diet-induced insulin-resistant hyperlipidemic hamsters. Metabolism 54 (2005) 403-409
10. Cases S., Smith S.J., Zheng Y.W., Myers H.M., Lear S.R., Sande E., et al. Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci U S A 95 (1998) 13018-13023
11. Cases S., Stone S., Zhou P., Yen E., Tow B., Lardizabal K.D., et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem 276 (2001) 38870-38876
12. Cases S., Zhou P., Shillingford J.M., Wiseman B.S., Fish J.D., Angle C.S., et al. Development of the mammary gland requires DGAT1 expression in stromal and epithelial tissues. Development 131 (2004) 3047-3055
13. Chakravarthy M.V., Pan Z., Zhu Y., Tordjman K., Schneider J.G., Coleman T., et al. "New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab 1 (2005) 309-322
14. Chen H.C. Enhancing energy and glucose metabolism by disrupting triglyceride synthesis: Lessons from mice lacking DGAT1. Nutr Metab (Lond) 3 (2006) 10
15. Chen H.C., and Farese Jr. R.V. DGAT and triglyceride synthesis: a new target for obesity treatment?. Trends Cardiovasc Med 10 (2000) 188-192
16. Chen H.C., and Farese Jr. R.V. Inhibition of triglyceride synthesis as a treatment strategy for obesity: Lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol 25 (2005) 482-486
17. Chen H.C., Smith S.J., Ladha Z., Jensen D.R., Ferreira L.D., Pulawa L.K., et al. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest 109 (2002) 1049-1055
18. Chen H.C., Smith S.J., Ladha Z., Jensen D.R., Ferreira L.D., Pulawa L.K., et al. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest 109 (2002) 1049-1055
19. Chen H.C., Stone S.J., Zhou P., Buhman K.K., and Farese Jr. R.V. Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl coenzyme a:diacylglycerol acyltransferase 1 in white adipose tissue. Diabetes 51 (2002) 3189-3195
20. Chen H.C., Rao M., Sajan M.P., Standaert M., Kanoh Y., Miura A., et al. Role of adipocyte-derived factors in enhancing insulin signaling in skeletal muscle and white adipose tissue of mice lacking Acyl CoA:diacylglycerol acyltransferase 1. Diabetes 53 (2004) 1445-1451
21. Chen N., Liu L., Zhang Y., Ginsberg H.N., and Yu Y.H. Whole-body insulin resistance in the absence of obesity in FVB mice with overexpression of DGAT1 in adipose tissue. Diabetes 54 (2005) 3379-3386
22. Choi C.S., Savage D.B., Kulkarni A., Yu X.X., Liu Z.X., Morino K., et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 282 (2007) 22678-22688
23. Choi C.S., Savage D.B., Kulkarni A., Yu X.X., Liu Z.X., Morino K., et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 282 (2007) 22678-22688
24. Coleman R.A., and Lee D.P. Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 43 (2004) 134-176
25. Francone O.L., Kalopissis A.D., and Griffaton G. Contribution of cytoplasmic storage triacylglycerol to VLDL-triacylglycerol in isolated rat hepatocytes. Biochim Biophys Acta 1002 (1989) 28-36
26. Goodpaster B.H., He J., Watkins S., and Kelley D.E. Skeletal muscle lipid content and insulin resistance: Evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 86 (2001) 5755-5761
27. Hamilton R.L., Wong J.S., Cham C.M., Nielsen L.B., and Young S.G. Chylomicron-sized lipid particles are formed in the setting of apolipoprotein B deficiency. J Lipid Res 39 (1998) 1543-1557
28. Heijboer A.C., Donga E., Voshol P.J., Dang Z.C., Havekes L.M., Romijn J.A., et al. Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice. J Lipid Res 46 (2005) 582-588
29. Hellerstein M.K., Schwarz J.M., and Neese R.A. Regulation of hepatic de novo lipogenesis in humans. Annu Rev Nutr 16 (1996) 523-557
30. Hirata T., Unoki H., Bujo H., Ueno K., and Saito Y. Activation of diacylglycerol O-acyltransferase 1 gene results in increased tumor necrosis factor-alpha gene expression in 3T3-L1 adipocytes. FEBS Lett 580 (2006) 5117-5121
31. Hu C.C., Qing K., and Chen Y. Diet-induced changes in stearoyl-CoA desaturase 1 expression in obesity-prone and -resistant mice. Obes Res 12 (2004) 1264-1270
32. Hubbard B.K., Enyedy I., Gilmore T.A., and Serrano-Wu M.H. Antisense and small-molecule modulation of diacylglycerol acyltransferase. Expert Opin Ther Patents 17 (2007) 1331-1339
33. Hudgins L.C., Hellerstein M., Seidman C., Neese R., Diakun J., and Hirsch J. Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet. J Clin Invest 97 (1996) 2081-2091
34. Kelpe C.L., Johnson L.M., and Poitout V. Increasing triglyceride synthesis inhibits glucose-induced insulin secretion in isolated rat islets of langerhans: A study using adenoviral expression of diacylglycerol acyltransferase. Endocrinology 143 (2002) 3326-3332
35. Krssak M., Falk Petersen K., Dresner A., DiPietro L., Vogel S.M., Rothman D.L., et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: A 1H NMR spectroscopy study. Diabetologia 42 (1999) 113-116
36. Kuerschner L., Moessinger C., and Thiele C. Imaging of lipid biosynthesis: How a neutral lipid enters lipid droplets. Traffic 9 (2008) 338-352
37. Lankester D., Brown A., and Zammit V. Use of cytosolic triacylglycerol hydrolysis products and of exogenous fatty cid for the synthesis of triacylglycerol secreted by cultured hepatocytes. J Lipid Res 32 (1998) 1635-1645
38. Lardizabal K.D., Mai J.T., Wagner N.W., Wyrick A., Voelker T., and Hawkins D.J. DGAT2 is a new diacylglycerol acyltransferase gene family: purification, cloning, and expression in insect cells of two polypeptides from Mortierella ramanniana with diacylglycerol acyltransferase activity. J Biol Chem 276 (2001) 38862-38869
39. Lardizabal K.D., Mai J.T., Wagner N.W., Wyrick A., Voelker T., and Hawkins D.J. DGAT2: A new diacylglycerol acyltransferase gene family: Purification, cloning and expression in insect cells of two polypeptides from Mortierella ramannniana with diacylglycerol acyltransferase activity. J Biol Chem (2001) M106168200
40. Levy D. Membrane proteins which exhibit multiple topological orientations. Essays Biochem 31 (1996) 49-60
41. Liang J.J., Oelkers P., Guo C., Chu P.C., Dixon J.L., Ginsberg H.N., et al. Overexpression of human diacylglycerol acyltransferase 1, acyl-coa:cholesterol acyltransferase 1, or acyl-CoA:cholesterol acyltransferase 2 stimulates secretion of apolipoprotein B-containing lipoproteins in McA-RH7777 cells. J Biol Chem 279 (2004) 44938-44944
42. Liu L., Zhang Y., Chen N., Shi X., Tsang B., and Yu Y.H. Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J Clin Invest 117 (2007) 1679-1689
43. Man W.C., Miyazaki M., Chu K., and Ntambi J. Co-localization of SCD1 and DGAT2: implying preference for endogenous monounsaturated fatty acids in triglyceride synthesis. J Lipid Res 47 (2006) 1928-1939
44. Matsuda D., and Tomota H. DGAT inhibitors for Obesity. Curr Opin Investig Drugs 8 (2007) 836-841
45. Meegalla R.L., Billheimer J.T., and Cheng D. Concerted elevation of acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) activity through independent stimulation of mRNA expression of DGAT1 and DGAT2 by carbohydrate and insulin. Biochem Biophys Res Commun 298 (2002) 317-323
46. Millar J.S., Stone S.J., Tietge U.J., Tow B., Billheimer J.T., Wong J.S., et al. Short-term hepatic overexpression of DGAT1 or DGAT2 in female mice increases hepatic triglyceride synthesis without changing VLDL triglyceride or ApoB production. J Lipid Res 47 (2006) 2297-2305
47. Miyazaki M., Kim Y.C., Gray-Keller M.P., Attie A.D., and Ntambi J.M. The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. J Biol Chem 275 (2000) 30132-30138
48. Moffitt J.H., Fielding B.A., Evershed R., Berstan R., Currie J.M., and Clark A. Adverse physicochemical properties of tripalmitin in beta cells lead to morphological changes and lipotoxicity in vitro. Diabetologia 48 (2005) 1819-1829
49. Montell E., Turini M., Marotta M., Roberts M., Noe V., Ciudad C.J., et al. DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. Am J Physiol Endocrinol Metab 280 (2001) E229-E237
50. Ogawa, N., Okuma, C., & Furukawa, N., (2007). US Patent 2007/0027093A1.
51. Orland M.D., Anwar K., Cromley D., Chu C.H., Chen L., Billheimer J.T., et al. Acyl coenzyme A dependent retinol esterification by acyl coenzyme A: diacylglycerol acyltransferase 1. Biochim Biophys Acta 1737 (2005) 76-82
52. Owen M., and Zammit V.A. Evidence for overt and latent forms of DGAT in rat liver microsomes. Implications for the pathways of triacylglycerol incorporation into VLDL. Biochem Soc Trans 25 (1997) 21S
53. Owen M., Corstorphine C.G., and Zammit V.A. Overt and latent activities of diacylglycerol acyltransferase in rat liver microsomes: Possible roles in very-low-density lipoprotein triacylglycerol secretion. Biochem J 323 (1997) 17-21
54. Ploegh H.L. A lipid-based model for the creation of an escape hatch from the endoplasmic reticulum. Nature 448 (2007) 435-438
55. Schenk S., and Horowitz J.F. Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. J Clin Invest 117 (2007) 1690-1698
56. Small D.M. Lateral chain packing in lipids and membranes. J Lipid Res 25 (1984) 1490-1500
57. Smith S.J., Cases S., Jensen D.R., Chen H.C., Sande E., Tow B., et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet 25 (2000) 87-90
58. Stone S.J., Levin M.C., and Farese Jr. R.V. Membrane topology and identification of key functional amino acid residues of murine acyl-CoA:diacylglycerol acyltransferase-2. J Biol Chem 281 (2006) 40273-40282
59. Stone S.J., Myers H.M., Watkins S.M., Brown B.E., Feingold K.R., Elias P.M., et al. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J Biol Chem 279 (2004) 11767-11776
60. Tsai J., Qiu W., Kohen-Avramoglu R., and Adeli K. MEK-ERK inhibition corrects the defect in VLDL assembly in HepG2 cells: Potential role of ERK in VLDL-ApoB100 particle assembly. Arterioscler Thromb Vasc Biol 27 (2007) 211-218
61. Waterman I.J., and Zammit V.A. Differential effects of fenofibrate or simvastatin treatment of rats on hepatic microsomal overt and latent diacylglycerol acyltransferase activities. Diabetes 51 (2002) 1708-1713
62. Wiggins D., and Gibbons G.F. The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density-lipoprotein and its response to hormones and sulphonylureas. Biochem J 284 (1992) 457-462
63. Wu X., Shang A., Jiang H., and Ginsberg H.N. Low rates of apoB secretion from HepG2 cells result from reduced delivery of newly synthesized triglyceride to a "secretion-coupled" pool. J Lipid Res 37 (1996) 1198-1206
64. Yamazaki T., Sasaki E., Kakinuma C., Yano T., Miura S., and Ezaki O. Increased very low density lipoprotein secretion and gonadal fat mass in mice overexpressing liver DGAT1. J Biol Chem 280 (2005) 21506-21514
65. Yang L.Y., Kuksis A., Myher J.J., and Steiner G. Origin of triacylglycerol moiety of plasma very low density lipoproteins in the rat: Structural studies. J Lipid Res 36 (1995) 125-136
66. Yang L.Y., Kuksis A., Myher J.J., and Steiner G. Contribution of de novo fatty acid synthesis to very low density lipoprotein triacylglycerols: Evidence from mass isotopomer distribution analysis of fatty acids synthesized from [2H6]ethanol. J Lipid Res 37 (1996) 262-274
67. Yen C.L., Monetti M., Burri B.J., and Farese Jr. R.V. The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters. J Lipid Res 46 (2005) 1502-1511
68. Yu Y.H., Zhang Y., Oelkers P., Sturley S.L., Rader D.J., and Ginsberg H.N. Posttranscriptional control of the expression and function of diacylglycerol acyltransferase-1 in mouse adipocytes. J Biol Chem 277 (2002) 50876-50884
69. Yu X.X., Murray S.F., Pandey S.K., Booten S.L., Bao D., Song X.Z., et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology 42 (2005) 362-371
70. Zammit V.A. Role of insulin in hepatic fatty acid partitioning: Emerging concepts. Biochem J 314 Pt 1 (1996) 1-14
71. Zhao G., Souers A.J., Voorbach M., Falls H.D., Droz B., Brodjian S., et al. Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor. J Med Chem 51 (2008) 380-383