Identification of a botanical inhibitor of intestinal diacylglyceride acyltransferase 1 activity via in vitro screening and a parallel, randomized, blinded, placebo-controlled clinical trial

Nutrition and Metabolism

Volumn 12, Issue 1, 2015, Pages

  Velliquette, Rodney A ^a   Grann, Kerry ^b   Missler, Stephen R ^a   Patterson, Jennifer ^a   Hu, Chun ^c   Gellenbeck, Kevin W ^c   Scholten, Jeffrey D ^a   Randolph, R Keith ^c  

^a Department of Analytical Sciences Amway R and D ^*  (United States)

^b Nutrition Product Development Food Beverages and Chewables Amway R and D   (United States)

^c Nutrilite   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACYLTRANSFERASE; ANTHOCYANIN; ANTILIPEMIC AGENT; APPLE PEEL EXTRACT; APRICOT NECTARINE EXTRACT; CATECHOL DERIVATIVE; DIACYLGLYCERIDE ACYLTRANSFERASE 1; DRUG METABOLITE; GALLIC ACID; GRAPE EXTRACT; PLACEBO; PLANT EXTRACT; POLYPHENOL; PROANTHOCYANIDIN; RASPBERRY EXTRACT; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ADULT; APPLE; APRICOT; ARTICLE; BLOOD LEVEL; CELL ASSAY; CELL FREE SYSTEM; CHROMATOGRAPHY; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG EFFECT; DRUG MECHANISM; DRUG RESPONSE; DRUG SCREENING; ENZYME ACTIVITY; ENZYME ASSAY; ENZYME INHIBITION; FEMALE; GRAPE; HUMAN; HYPERTRIGLYCERIDEMIA; IC50; IN VITRO STUDY; MAJOR CLINICAL STUDY; MALE; MICROSOME; MIDDLE AGED; NECTARINE; OBESITY; PHYTOCHEMISTRY; PLANT LEAF; RANDOMIZED CONTROLLED TRIAL; RASPBERRY;

MALUS X DOMESTICA; RUBUS IDAEUS; VITACEAE;

EID: 84938692142     PISSN: None     EISSN: 17437075     Source Type: Journal    
DOI: 10.1186/s12986-015-0025-2     Document Type: Article

References (59)

1. Swinburn BA, Sacks G, Hall KD, McPherson K, Finegood DT, Moodie ML, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet. 2011;378:804-14.
2. Chun OK, Chung SJ, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr. 2007;137:1244-52.
3. Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292-333.
4. Boren J, Matikainen N, Adiels M, Taskinen MR. Postprandial hypertriglyceridemia as a coronary risk factor. Clin Chim Acta. 2014;431:131-42.
5. Katsanos CS. Clinical considerations and mechanistic determinants of postprandial lipemia in older adults. Adv Nutr. 2014;5:226-34.
6. Chan DC, Pang J, Romic G, Watts GF. Postprandial hypertriglyceridemia and cardiovascular disease: current and future therapies. Curr Atheroscler Rep. 2013;15:309.
7. Zilversmit DB. Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins. Clin Chem. 1995;41:153-8.
8. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation. 1979;60:473-85.
9. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298:309-16.
10. Cohn JS. Are we ready for a prospective study to investigate the role of chylomicrons in cardiovascular disease? Atheroscler Suppl. 2008;9:15-8.
11. Redgrave TG. Chylomicrons in disease-future challenges Invited keynote address. Atheroscler Suppl. 2008;9:3-6.
12. DeVita RJ, Pinto S. Current status of the research and development of diacylglycerol O-acyltransferase 1 (DGAT1) inhibitors. J Med Chem. 2013;56:9820-5.
13. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299-308.
14. Sasase T, Morinaga H, Yamamoto H, Ogawa N, Matsui K, Miyajima K, et al. Increased fat absorption and impaired fat clearance cause postprandial hypertriglyceridemia in Spontaneously Diabetic Torii rat. Diabetes Res Clin Pract. 2007;78:8-15.
15. Ceriello A, Quagliaro L, Piconi L, Assaloni R, Da Ros R, Maier A, et al. Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment. Diabetes. 2004;53:701-10.
16. Bae JH, Schwemmer M, Lee IK, Lee HJ, Park KR, Kim KY, et al. Postprandial hypertriglyceridemia-induced endothelial dysfunction in healthy subjects is independent of lipid oxidation. Int J Cardiol. 2003;87:259-67.
17. Bae JH, Bassenge E, Kim KB, Kim YN, Kim KS, Lee HJ, et al. Postprandial hypertriglyceridemia impairs endothelial function by enhanced oxidant stress. Atherosclerosis. 2001;155:517-23.
18. Teno S, Uto Y, Nagashima H, Endoh Y, Iwamoto Y, Omori Y, et al. Association of postprandial hypertriglyceridemia and carotid intima-media thickness in patients with type 2 diabetes. Diabetes Care. 2000;23:1401-6.
19. Mitsuguchi Y, Ito T, Ohwada K. Pathologic findings in rabbit models of hereditary hypertriglyceridemia and hereditary postprandial hypertriglyceridemia. Comp Med. 2008;58:465-80.
20. Botham KM, Wheeler-Jones CP. Postprandial lipoproteins and the molecular regulation of vascular homeostasis. Prog Lipid Res. 2013;52:446-64.
21. Schwander F, Kopf-Bolanz KA, Buri C, Portmann R, Egger L, Chollet M, et al. A Dose-response Strategy Reveals Differences between Normal-Weight and Obese Men in Their Metabolic and Inflammatory Responses to a High-Fat Meal. J Nutr. 2014;144:1517-23.
22. Yen CL, Stone SJ, Koliwad S, Harris C, Farese Jr RV. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res. 2008;49:2283-301.
23. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet. 2000;25:87-90.
24. Ables GP, Yang KJ, Vogel S, Hernandez-Ono A, Yu S, Yuen JJ, et al. Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying. J Lipid Res. 2012;53:2364-79.
25. Lee B, Fast AM, Zhu J, Cheng JX, Buhman KK. Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1-/- mice. J Lipid Res. 2010;51:1770-80.
26. Birch AM, Buckett LK, Turnbull AV. DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr Opin Drug Discov Devel. 2010;13:489-96.
27. Yeh VS, Beno DW, Brodjian S, Brune ME, Cullen SC, Dayton BD, et al. Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1. J Med Chem. 2012;55:1751-7.
28. Cheng D, Iqbal J, Devenny J, Chu CH, Chen L, Dong J, et al. Acylation of acylglycerols by acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1). Functional importance of DGAT1 in the intestinal fat absorption. J Biol Chem. 2008;283:29802-11.
29. Schober G, Arnold M, Birtles S, Buckett LK, Pacheco-Lopez G, Turnbull AV, et al. Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats. J Lipid Res. 2013;54:1369-84.
30. Langhans W, Leitner C, Arnold M. Dietary fat sensing via fatty acid oxidation in enterocytes: possible role in the control of eating. Am J Physiol Regul Integr Comp Physiol. 2011;300:R554-65.
31. Lin HV, Chen D, Shen Z, Zhu L, Ouyang X, Vongs A, et al. Diacylglycerol acyltransferase-1 (DGAT1) inhibition perturbs postprandial gut hormone release. PLoS One. 2013;8:e54480.
32. Kolovou GD, Mikhailidis DP, Kovar J, Lairon D, Nordestgaard BG, Ooi TC, et al. Assessment and clinical relevance of non-fasting and postprandial triglycerides: an expert panel statement. Curr Vasc Pharmacol. 2011;9:258-70.
33. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502.
34. Qi J, Lang W, Giardino E, Caldwell GW, Smith C, Minor LK, et al. High-content assays for evaluating cellular and hepatic diacylglycerol acyltransferase activity. J Lipid Res. 2010;51:3559-67.
35. Maciejewski BS, LaPerle JL, Chen D, Ghosh A, Zavadoski WJ, McDonald TS, et al. Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans. Am J Physiol Gastrointest Liver Physiol. 2013;304:G958-69.
36. Denison H, Nilsson C, Lofgren L, Himmelmann A, Martensson G, Knutsson M, et al. Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial. Diabetes Obes Metab. 2014;16:334-43.
37. Denison H, Nilsson C, Kujacic M, Lofgren L, Karlsson C, Knutsson M, et al. Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study. Diabetes Obes Metab. 2013;15:136-43.
38. Cao J, Zhou Y, Peng H, Huang X, Stahler S, Suri V, et al. Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases. J Biol Chem. 2011;286:41838-51.
39. Hiramine Y, Tanabe T. Characterization of acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) enzyme of human small intestine. J Physiol Biochem. 2011;67:259-64.
40. Serrano-Wu MH, Coppola GM, Gong Y, Neubert AD, Chatelain R, Clairmont KB, et al. Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial Triglycerides. ACS Med Chem Lett. 2012;3:411-5.
41. King AJ, Segreti JA, Larson KJ, Souers AJ, Kym PR, Reilly RM, et al. In vivo efficacy of acyl CoA: diacylglycerol acyltransferase (DGAT) 1 inhibition in rodent models of postprandial hyperlipidemia. Eur J Pharmacol. 2010;637:155-61.
42. Yang J, Xiao YY. Grape phytochemicals and associated health benefits. Crit Rev Food Sci Nutr. 2013;53:1202-25.
43. Dohadwala MM, Vita JA. Grapes and cardiovascular disease. J Nutr. 2009;139:1788S-93.
44. Joshi SS, Kuszynski CA, Bagchi D. The cellular and molecular basis of health benefits of grape seed proanthocyanidin extract. Curr Pharm Biotechnol. 2001;2:187-200.
45. Lefevre M, Wiles JE, Zhang X, Howard LR, Gupta S, Smith AA, et al. Gene expression microarray analysis of the effects of grape anthocyanins in mice: a test of a hypothesis-generating paradigm. Metabolism. 2008;57:S52-7.
46. Georgiev V, Ananga A, Tsolova V. Recent advances and uses of grape flavonoids as nutraceuticals. Nutrients. 2014;6:391-415.
47. Xia EQ, Deng GF, Guo YJ, Li HB. Biological activities of polyphenols from grapes. Int J Mol Sci. 2010;11:622-46.
48. Yadav M, Jain S, Bhardwaj A, Nagpal R, Puniya M, Tomar R, et al. Biological and medicinal properties of grapes and their bioactive constituents: an update. J Med Food. 2009;12:473-84.
49. Chuang CC, McIntosh MK. Potential mechanisms by which polyphenol-rich grapes prevent obesity-mediated inflammation and metabolic diseases. Annu Rev Nutr. 2011;31:155-76.
50. Ali K, Maltese F, Choi Y, Verpoorte R. Metabolic constituents of grapevine and grape-derived products. Phytochemistry Reviews. 2010;9:357-78.
51. Klein A, Wrulich OA, Jenny M, Gruber P, Becker K, Fuchs D, et al. Pathway-focused bioassays and transcriptome analysis contribute to a better activity monitoring of complex herbal remedies. BMC Genomics. 2013;14:133.
52. Stevenson DE, Hurst RD. Polyphenolic phytochemicals - just antioxidants or much more? Cell Mol Life Sci. 2007;64:2900-16.
53. Milella RA, Antonacci D, Crupi P, Incampo F, Carrieri C, Semeraro N, et al. Skin extracts from 2 Italian table grapes (Italia and Palieri) inhibit tissue factor expression by human blood mononuclear cells. J Food Sci. 2012;77:H154-9.
54. Forester SC, Waterhouse AL. Identification of Cabernet Sauvignon anthocyanin gut microflora metabolites. J Agric Food Chem. 2008;56:9299-304.
55. Cardona F, Andres-Lacueva C, Tulipani S, Tinahones FJ, Queipo-Ortuno MI. Benefits of polyphenols on gut microbiota and implications in human health. J Nutr Biochem. 2013;24:1415-22.
56. Hidalgo M, Oruna-Concha MJ, Kolida S, Walton GE, Kallithraka S, Spencer JP, et al. Metabolism of anthocyanins by human gut microflora and their influence on gut bacterial growth. J Agric Food Chem. 2012;60:3882-90.
57. Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem. 2001;276:38870-6.
58. Haas JT, Winter HS, Lim E, Kirby A, Blumenstiel B, DeFelice M, et al. DGAT1 mutation is linked to a congenital diarrheal disorder. J Clin Invest. 2012;122:4680-4.
59. Little TJ, Horowitz M, Feinle-Bisset C. Modulation by high-fat diets of gastrointestinal function and hormones associated with the regulation of energy intake: implications for the pathophysiology of obesity. Am J Clin Nutr. 2007;86:531-41.