DGAT inhibitors for obesity

Current Opinion in Investigational Drugs

Volumn 8, Issue 10, 2007, Pages 836-841

  Matsuda, D ^a   Tomoda, H ^a  

^a KITASATO UNIVERSITY   (Japan)

Author keywords

DGAT1; DGAT2; Diacylglycerol acyltransferase; Inhibitor; Isozyme; Obesity

Indexed keywords

15,16 DIHYDROTANSHINONE; ACYLTRANSFERASE INHIBITOR; AMIDEPSINE A; AMIDEPSINE B; AMIDEPSINE C; AMIDEPSINE D; AMIDEPSINE E; BETULIC ACID; COROSOLIC ACID; CRYPTOTANSHINONE; DIACYLGLYCEROL ACYLTRANSFERASE; DIACYLGLYCEROL ACYLTRANSFERASE 1; DIACYLGLYCEROL ACYLTRANSFERASE 2; DIACYLGLYCEROL ACYLTRANSFERASE INHIBITOR; EVOCARPINE; KURARIDIN; KURARINOL; KURARINONE; KUSHENOL H; KUSHENOL K; METHYLURSOLATE; OLEANOLIC ACID; PIPERNONALINE; ROSELIPIN 1A; ROSELIPIN 1B; ROSELIPIN 2A; ROSELIPIN 2B; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERY LOW DENSITY LIPOPROTEIN; XANTHOHUMOL B;

DRUG EFFECT; DRUG POTENCY; DRUG SELECTIVITY; ENZYME INHIBITION; GENE MUTATION; HUMAN; OBESITY; PROTEIN BLOOD LEVEL; PROTEIN FUNCTION; PROTEIN SYNTHESIS; REVIEW; STEATOSIS; TREATMENT OUTCOME;

ADIPOCYTES; ANIMALS; ANTI-OBESITY AGENTS; DIACYLGLYCEROL O-ACYLTRANSFERASE; FATTY LIVER; HUMANS; LIPOPROTEINS, VLDL; OBESITY;

EID: 34848834771     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (35)

1. Bray GA, Ryan DH: Drug treatment of the overweight patient. Gastroenterology (2007) 132(6):2239-2252.
2. Lehner R, Kuksis A: Biosynthesis of triacylglycerols. Prog Lipid Res (1996) 35(2):169-201.
3. Cases S, Smith SJ, Zheng Y-W, Myers HM, Lear SR, Sande E, Novak S, Collins C, Welch CB, Lusis AJ, Erickson SK, Farese RV Jr: Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci USA (1998) 95(22):13018-13023. • This is the first report of the cloning of the DGAT gene in mammals and its characteristics.
4. Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL: Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes. J Biol Chem (1998) 273(41):26765-26771.
5. Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, Voelker T, Farese RV Jr: Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem (2001) 276(42):38870- 38876.
6. Tomoda H, Doi T: Discovery and combinatorial synthesis of fungal metabolites beauveriolides, novel anti-atherosclerotic agents. Acc Chem Res (2007):doi 10.1021/ar700117b. •• This review describes the screening system of lipid droplet formation in macrophages for the discovery of fungal beauverilolide, its anti-atherogenic activity, mode of action and combinatorial synthesis.
7. Stone SJ, Levin MC, Farese RV Jr: Membrane topology and identification of key functional amino acid residues of murine acyl-CoA:diacylglycerol acyltransferase-2. J Biol Chem (2006) 281(52):40273-40282. • DGAT2 is an integral membrane protein. Both the N and C termini are oriented in the cytosol and amino acids 66 to 115, and comprise of two transmembrane domains or a single domain that is embedded in the membrane bilayer.
8. Tomoda H, Omura S: Potential therapeutics for obesity and atherosclerosis: Inhibitors of neutral lipid metabolism from microorganisms. Pharmacol Ther (2007) 115(3):375-389. •• This review summarizes the microbial inhibitors of DGAT and acyl-CoA:cholesterol acyltransferase and describes their potential in the treatment of obesity.
9. Stone SJ, Myers HM, Watkins SM, Brown BE, Feingold KR, Elias PM, Farese RV Jr: Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J Biol Chem (2004) 279(12):11767-11776. •• DGAT2 is involved in the major pathway of TG synthesis in mice. This paper provides significant insights into the functional differences between DGAT1 and DGAT2.
10. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, Farese RV Jr: Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking DGAT. Nat Genet (2000) 25(1):87-90.
11. Chen HC, Smith SJ, Ladha Z, Jensen DR, Ferreira LD, Pulawa LK, McGuire JG, Pitas RE, Eckel RH, Farese RV Jr: Increased insulin and leptin sensitivity in mice lacking acyl-CoA:diacylglycerol acyltransferase 1. J Clin Invest (2002) 109(8):1049-1055. • This paper provides new insights into how alterations in triglyceride synthesis affects insulin and leptin sensitivity in mice.
12. Chen HC, Ladha Z, Smith SJ, Farese RV Jr: Analysis of energy expenditure at different ambient temperatures in mice lacking DGAT1. Am J Physiol Endocrinol Metab (2003) 284(1):E213-E218.
13. Friedel S, Reichwald K, Scherag A, Brumm H, Wermter AK, Fries HR, Koberwitz K, Wabitsch M, Meitinger T, Platzer M, Biebermann H et al: Mutation screen and association studies in the diacylglycerol O-acyltransferase homolog 2 gene (DGAT2), a positional candidate gene for early onset obesity on chromosome 11q13. BMC Genet (2007) 8:17-25.
14. Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D 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 (2007) 282(31):22678-22688.
15. Chen HC, Farese RV Jr: Inhibition of triglyceride synthesis as a treatment strategy for obesity: Lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol (2005) 25(3):482-486. •• This review describes the prospect of DGAT1 as a pharmaceutical target from studies of DGAT1-knockout mice.
16. Tomoda H, Ito M, Tabata N, Masuma R, Yamaguchi Y, Omura S: Amidepsines, inhibitors of diacylglycerol acyltransferase produced by Humicola sp. FO-2942. I. Production, isolation and biological properties. J Antibiot (1995) 48(9):937-941.
17. Tomoda H, Tabata N, Ito M, Omura S: Amidepsines, inhibitors of diacyl glycerol acyltransferase produced by Humicola sp. FO-2942. II. Structure elucidation of amidepsines A, B and C. J Antibiot (1995) 48(9):942-947.
18. Tomoda H, Yamaguchi Y, Tabata N, Kobayashi T, Masuma R, Tanaka H, Omura S: Amidepsine E, an inhibitor of diacylglycerol acyltransferase produced by Humicola sp. FO-5969. J Antibiot (1996) 49(9):929-931.
19. Omura S, Tomoda H, Tabata N, Ohyama Y, Abe T, Namikoshi M: Roselipins, novel fungal metabolites having a highly methylated fatty acid modified with a mannose and an arabinitol. J Antibiot (1999) 52(6):586-589.
20. Tomoda H, Ohyama Y, Abe T, Tabata N, Namikoshi M, Yamaguchi Y, Masuma R, Omura S: Roselipins, inhibitors of diacylglycerol acyltransferase, produced by Gliocladium roseum KF-1040. J Antibiot (1999) 52(8):689-694.
21. Tabata N, Ohyama Y, Tomoda H, Abe T, Namikoshi M, Omura S: Structure elucidation of roselipins, inhibitors of diacylglycerol acyltransferase produced by Gliocladium roseum KF-1040. J Antibiot (1999) 52(9):815-826.
22. Elix JA, Jayanthi VK, Leznoff CC: 2,4-Di-O-methylgyrophoric acid and 2,4,5-tri-O-methylhiascic acid. New tridepsides from Parmelia damaziana. Aust J Chem (1981) 34(8):1757-1761.
23. Tabata N, Ito M, Tomoda H, Omura S: Xanthohumols, diacylglycerol acyltransferase inhibitors, from Humulus lupulus. Phytochemistry (1997) 46(4):683-687.
24. Ko JS, Rho MC, Chung MY, Song HY, Kang JS, Kim K, Lee HS, Kim YK: Quinolone alkaloids, diacylglycerol acyltransferase inhibitors from the fruits of Evodia rutaecarpa. Planta Med (2002) 68(12):1131-1133.
25. Ko JS, Ryu SY, Kim YS, Chung MY, Kang JS, Rho MC, Lee HS, Kim YK: Inhibitory activity of diacylglycerol acyltransferase by tanshinones from the root of Salvia miltiorrhiza. Arch Pharm Res (2002) 25(4):446-448.
26. Lee SW, Kim K, Rho MC, Chung MY, Kim YH, Lee S, Lee HS, Kim YK: New polyacetylenes, DGAT inhibitors from the roots of Panax ginseng. Planta Med (2004) 70(3):197-200.
27. Chung MY, Rho MC, Ko JS, Ryu SY, Jeune KH, Kim K, Lee HS, Kim YK: In vitro inhibition of diacylglycerol acyltransferase by prenylflavonoids from Sophora flavescens. Planta Med (2004) 70(3):258-260.
28. Dat NT, Cai XF, Rho MC, Lee HS, Bae K, Kim YH: The inhibition of diacylglycerol acyltransferase by terpenoids from Youngia koidzumiana. Arch Pharm Res (2005) 28(2):164-168.
29. Chung MY, Rho MC, Lee SW, Park HR, Kim K, Lee IA, Kim DH, Jeune KH, Lee HS, Kim YK: Inhibition of diacylglycerol acyltransferase by betulinic acid from Alnus hirsuta. Planta Med (2006) 72(3):267-269.
30. Lee SW, Rho MC, Park HR, Choi JH, Kang JY, Lee JW, Kim K, Lee HS, Kim YK: Inhibition of diacylglycerol acyltransferase by alkamides isolated from the fruits of Piper longum and Piper nigrum. J Agric Food Chem (2006) 54(26):9759-9763.
31. Tomoda H, Igarashi K, Cyong JC, Omura S: Evidence for an essential role of long chain acyl-CoA synthetase in animal cell proliferation. Inhibition of long chain acyl-CoA synthetase by triacsins caused inhibition of Raji cell proliferation. J Biol Chem (1991) 266(7):4214-4219.
32. Clapham JC, Arch JR: Thermogenic and metabolic antiobesity drugs: Rationale and opportunities. Diabetes Obes Metab (2007) 9(3):259-275. •• This review describes not only DGAT, but also several other enzymes involved in fatty acid metabolism as potential targets of antiobesity drugs.
33. JAPAN TOBACCO INC; TULARIK INC (Fox BM, Iio K, Inaba T, Kayser F, Li K, Sagawa S, Tanaka M, Yoshida A): New pyrrolo[1,2-b]pyridazine compounds are diacylglycerol acyltransferase modulators - useful for the treatment of obesity, diabetes mellitus, syndrome X, hypercholesterolemia, liver disease, atherosclerosis, arteriosclerosis, myocardial infarction, cerebrovascular ischemia, cancer and restenosis. WO-2005013907 (2005).
34. BAYER PHARMACEUTICALS CORP (Smith R, Lowe D, Coish P, Wang G, Patel M, Bondar G): New aryl alkyl acid derivatives are diacylglycerol O-acyltransferase type 1 inhibitors - useful for treating obesity and obesity-related disorders. WO-2006113919 (2006).
35. F HOFFMANN-LA ROCHE LTD (Michoud C): New N,N′-diacylhydrazide derivatives are DGAT inhibitors - useful for the treatment of obesity, non-insulin-dependent diabetes and metabolic syndrome. WO-2006120125 (2006).