Lipid metabolic enzymes: Emerging drug targets for the treatment of obesity

Nature Reviews Drug Discovery

Volumn 3, Issue 8, 2004, Pages 695-710

  Shi, Yuguang ^a   Burn, Paul ^b  

^a ELI LILLY AND COMPANY   (United States)

^b BAYER CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (3 CARBOXYPHENYL) 3,7 DIMETHYL 9 (2,6,6 TRIMETHYL 1 CYCLOHEXENYL) 2,4,6,8 NONATETRAENOIC ACID; ACYL COENZYME A DESATURASE; ACYLGLYCEROL PALMITOYLTRANSFERASE; AMIDEPSINE A; ANTIOBESITY AGENT; AVASIMIBE; CARNITINE PALMITOYLTRANSFERASE; CERULENIN; CHOLESTEROL ACYLTRANSFERASE; CP 346086; CP 610431; CT 32458; CT 32615; DIACYLGLYCEROL ACYLTRANSFERASE; EBELACTONE A; ETOMOXIR; FATTY ACID; FATTY ACID SYNTHASE; GLYCEROL 3 PHOSPHATE ACYLTRANSFERASE; IMPLITAPIDE; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN; PHOSPHOLIPASE A2; RO 23 9358; TETRAHYDROLIPSTATIN; THIOLACTOMYCIN; TRIACYLGLYCEROL; TRIACYLGLYCEROL LIPASE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERY LOW DENSITY LIPOPROTEIN; XANTHOHUMOL; ENZYME INHIBITOR; LACTONE;

ADIPOCYTE; CLINICAL TRIAL; DRUG MECHANISM; DRUG STRUCTURE; DRUG TARGETING; ENERGY ABSORPTION; ENERGY CONVERSION; ENERGY EXPENDITURE; ENZYME ACTIVITY; ENZYME INHIBITION; FAT INTAKE; FATTY ACID OXIDATION; FATTY ACID TRANSPORT; FOOD INTAKE; HUMAN; LIPID METABOLISM; LIPID OXIDATION; MOLECULAR MECHANICS; NONHUMAN; OBESITY; PRIORITY JOURNAL; REVIEW; DIGESTION; DRUG ANTAGONISM; ENZYMOLOGY; METABOLISM;

ANTI-OBESITY AGENTS; DIETARY FATS; DIGESTION; ENZYME INHIBITORS; HUMANS; LACTONES; LIPASE; LIPID METABOLISM; OBESITY;

EID: 4344598315     PISSN: 14741776     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrd1469     Document Type: Review

References (163)

1. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity: the evidence report (US Government Press, Washington DC, 1998).
2. Campfield, L. A., Smith, F. J. & Burn, P. Strategies and potential molecular targets for obesity treatment. Science 280, 1383-1387 (1998).
3. Hill, J. O., Melanson, E. L. & Wyatt, H. T. Dietary fat intake and regulation of energy balance: implications for obesity. J. Nutr. 130, 284S-288S (2000).
4. Carriere, F. et al. Gastric and pancreatic lipase levels during a test meal in dogs. Scand. J. Gastroenterol. 28, 443-454 (1993).
5. Nordskog, B. K., Phan, C. T., Nutting, D. F. & Tso, P. An examination of the factors affecting intestinal lymphatic transport of dietary lipids. Adv. Drug Deliv. Rev. 50, 21-44 (2001).
6. Phan, C. T. & Tso, P. Intestinal lipid absorption and transport. Front. Biosci. 6, D299-D319 (2001).
7. Kawai, T. & Fushiki, T. Importance of lipolysis in oral cavity for orosensory detection of fat. Am. J. Phys. Regul. Integr. Comp. Physiol. 285, R447-R454 (2003).
8. Miled, N. et al. Digestive lipases: from three-dimensional structure to physiology. Biochimie 82, 973-986 (2000).
9. Ghishan, F. K., Moran, J. R., Durie, P. R. & Greene, H. L. Isolated congenital lipase-colipase deficiency. Gastroenterology 86, 1580-1582 (1984).
10. Carriere, F., Barrowman, J. A., Verger, R. & Laugier, R. Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. Gastroenterology 105, 876-888 (1993).
11. Borgstrom, B. Binding of pancreatic colipase to interfaces: effects of detergents. FEBS Lett. 71, 201-204 (1976).
12. Bowyer, R. C., Rowston, W. M., Jehanli, A. M., Lacey, J. H. & Hermon-Taylor, J. Effect of a satiating meal on the concentrations of procolipase propeptide in the serum and urine of normal and morbidly obese subjects. Gut 34, 1520-1525 (1993).
13. Weibel, E. K., Hadvary, P., Hochuli, E., Kupfer, E. & Lengsfeld, H. Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. I. Producing organism, fermentation, isolation and biological activity. J. Antibiot. 40, 1081-1085 (1987).
14. Bitou, N., Ninomiya, M., Tsujita, T. & Okuda, H. Screening of lipase inhibitors from marine algae. Lipids 34, 441-445 (1999).
15. Zhi, J., Mulligan, T. E. & Hauptman, J. B. Long-term systemic exposure of orlistat, a lipase inhibitor, and its metabolites in obese patients. J. Clin. Pharmacol. 39, 41-46 (1999).
16. Hadvary, P., Sidler, W., Meister, W., Vetter, W. & Wolfer, H. The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase. J. Biol. Chem. 266, 2021-2027 (1991).
17. Lucas, C. P., Boldrin, M. N. & Reaven, G. M. Effect of orlistat added to diet (30% of calories from fat) on plasma lipids, glucose, and insulin in obese patients with hyper-cholesterolemia. Am. J. Cardiol. 91, 961-964 (2003).
18. Padwal, R., Li, S. K. & Lau, D. C. W. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int. J. Obes. 27, 1437-1446 (2003).
19. Hanefeld, M. & Sachse, G. The effects of orlistat on body weight and glycaemic control in overweight patients with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes Obes. Metab. 4, 415-423 (2002).
20. Carey, M. C., Small, D. M. & Bliss, C. M. Lipid digestion and absorption. Annu. Rev. Physiol. 45, 651-677 (1983).
21. Huggins, K. W., Boileau, A. C. & Hui, D. Y. Protection against diet-induced obesity and obesity-related insulin resistance in group 1B PLA2-deficient mice. Am. J. Physiol. Endocrinol. Metab. 283, E994-E1001 (2002).
22. Richmond, B. L. et al. Compensatory phospholipid digestion is required for cholesterol absorption in pancreatic phospholipase A(2)-deficient mice. Gastroenterology 120, 1193-1202 (2001).
23. Chang, T. M., Chang, C. H., Wagner, D. R. & Chey, W. Y. Porcine pancreatic phospholipase A2 stimulates secretin release from secretin-producing cells. J. Biol. Chem. 274, 10758-10764 (1999).
24. Ma, T. et al. Defective dietary fat processing in transgenic mice lacking aquaporin-1 water channels. Am. J. Physiol. Cell. Physiol. 280, C126-C134 (2001).
25. Richmond, B. L. & Hui, D. Y. Molecular structure and tissue-specific expression of the mouse pancreatic phospholipase A(2) gene. Gene 244, 65-72 (2000).
26. Murakami, M. & Kudo, I. Phospholipase A2. J. Biochem. 131, 285-292 (2002).
27. Yuan, C. & Tsai, M. Pancreatic phospholipase A(2): new views on old issues. Biochim. Biophys. Acta 23, 2-3 (1999).
28. Mihelich, E. D. & Schevil R. W. Structure-based design of a new class of anti-inflammatory drugs: secretory phospholipase A(2) inhibitors, SPI. Biochim. Biophys. Acta 23, 233-238 (1999).
29. Niessen, H. W. M., Krijnen, P. A. J., Visser, C. A., Meijer, C. & Hack, C. E. Type II secretory phospholipase A2 in cardiovascular disease: a mediator in atherosclerosis and ischemic damage to cardiomyocytes? Cardiovasc. Res. 60, 68-77 (2003).
30. Yuan, C., Byeon, I. J., Poi, M. J. & Tsai, M. D. Structural analysis of phospholipase A2 from functional perspective. 2. Characterization of a molten globule-like state induced by site-specific mutagenesis. Biochemistry 38, 2919-2929 (1999).
31. Hajri, T. & Abumrad, N. A. Fatty acid transport across membranes: relevance to nutrition and metabolic pathology. Annu. Rev. Nutr. 22, 383-415 (2002).
32. Kamp, F. et al. Rapid flip-flop of oleic acid across the plasma membrane of adipocytes. J. Biol. Chem. 278, 7988-7995 (2003).
33. Vassileva, G., Huwyler, L., Poirier, K., Agellon, L. B. & Toth, M. J. The intestinal fatty acid binding protein is not essential for dietary fat absorption in mice, FASEB J. 14, 2040-2046 (2000).
34. Abumrad, N. A., el-Maghrabi, M. R., Amid, E. Z., Lopez, E. & Grimaldi, P. A. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. J. Biol. Chem. 268, 17665-17668 (1993).
35. Chen, M., Yang, Y., Braunstein, E., Georgeson, K. E. & Harmon, C. M. Gut expression and regulation of FAT/CD36: possible role in fatty acid transport in rat enterocytes. Am. J. Physiol. Endocrinol. Metab. 281, E916-E923 (2001).
36. Poirier, H., Degrace, P., Niot I., Bernard, A. & Besnard, P. Localization and regulation of the putative membrane fatty-acid transporter (FAT) in the small intestine. Comparison with fatty acid-binding proteins (FABP). Eur. J. Biochem. 238, 368-373 (1996).
37. Greenwalt, D. E., Scheck, S. H. & Rhinehart-Jones, T. Heart CD36 expression is increased in murine models of diabetes and in mice fed a high fat diet. J. Clin. Invest. 96, 1382-1388 (1995).
38. Goudriaan, J. R. et al. Intestinal lipid absorption is not affected in CD36 deficient mice. Mol. Cell. Biochem. 239, 199-202 (2002).
39. Schaffer, J. E. & Lodish, H. F. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein. Cell 79, 427-436 (1994).
40. Gimeno, R. E. et al. Targeted deletion of fatty acid transport protein-4 results in early embryonic lethality. J. Biol. Chem. 278, 49512-49516 (2003).
41. Herrmann, T. et al. Mouse fatty acid transport protein 4 (FATP4): characterization of the gene and functional assessment as a very long chain acyl-CoA synthetase. Gene 270, 31-40 (2001).
42. Coleman, R. A. & Lee, D. P. Enzymes of triacylglycerol synthesis and their regulation. Prog. Lipid Res. 43, 134-176 (2004).
43. Polheim, D., David, J. S., Schultz, F. M., Wylie, M. B. & Johnston, J. M. Regulation of triglyceride biosynthesis in adipose and intestinal tissue. J. Lipid Res. 14, 415-421 (1973).
44. Yen, C. L., Stone, S. J., Cases, S., Zhou, P. & Farese, R. V. Jr. Identification of a gene encoding MGAT1, a monoacylglycerol acyltransferase. Proc. Natl Acad. Sci. USA 99, 8512-8517 (2002).
45. Cao, J., Lockwood, J., Burn, P. & Shi, Y. Cloning and functional characterization of a mouse intestinal Acyl-CoA:monoacylglycerol acyltransferase, MGAT2. J. Biol. Chem. 278, 13860-13866 (2003).
46. Cao, J. et al. 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. J. Biol. Chem. 279, 18878-18886 (2004).
47. Cheng, D. et al. Identification of acyl coenzyme A:monoacylglycerol acyltransferase 3, an intestinal specific enzyme implicated in dietary fat absorption. J. Biol. Chem. 278, 13611-13614 (2003).
48. Yen, C. L. & Farese, R. V. Jr. MGAT2, a monoacylglycerol acyltransferase expressed in the small intestine. J. Biol. Chem. 278, 18532-18537 (2003).
49. Lockwood, J. F., Cao, J., Burn, P. & Shi, Y. Human intestinal monoacylglycerol acyltransferase: differential features in tissue expression and activity. Am. J. Physiol. Endocrinol. Metab. 285, E927-E937 (2003).
50. Mostafa, N., Bhat, B. G. & Coleman, R. A. Increased hepatic monoacylglycerol acyltransferase activity in streptozotocin-induced diabetes: characterization and comparison with activities from adult and neonatal rat liver. Biochim. Biophys. Acta 1169, 189-195 (1993).
51. Luan, Y. et al. Pathogenesis of obesity by food restriction in OLETF rats: increased intestinal monoacylglycerol acyltransferase activities may be a crucial factor. Diabetes Res. Clin. Prac. 57, 75-82 (2002).
52. Sudhop, T. & von Bergmann, K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 62, 2333-2347 (2002).
53. Hideshima, T. et al. Antitumor activity of lysophosphatidic acid acyltransferase-β inhibitors, a novel class of agents, in multiple myeloma. Cancer Res. 63, 8428-8436 (2003).
54. Coon, M. et al. Inhibition of lysophosphatidic acid acyltransferase disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells, Mol. Cancer Ther. 2, 1067-1078 (2003).
55. Thomson, A. B., Cheeseman, C. I., Keelan, M., Fedorak, R. & Clandinin, M. T. Crypt cell production rate, enterocyte turnover time and appearance of transport along the jejunal villus of the rat. Biochim. Biophys. Acta. 1191, 197-204 (1994).
56. Bakillah, A. & El Abbouyi, A. The role of microsomal triglyceride transfer protein in lipoprotein assembly: an update. Front. Biosci. 8, D294-D305 (2003).
57. Hussain, M. M. A proposed model for the assembly of chylomicrons. Atherosclerosis 148, 1-15 (2000).
58. Wetterau, J. R. et al. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. Science 282, 751-754 (1998).
59. Ksander, G. M. et al. Diaminoindanes as microsomal triglyceride transfer protein inhibitors. J. Med. Chem. 44, 4677-4687 (2001).
60. Shiomi, M. & Ito, T. MTP inhibitor decreases plasma cholesterol levels in LDL receptor-deficient WHHL rabbits by lowering the VLDL secretion. Eur. J. Pharmacol. 431, 127-131 (2001).
61. Robl, J. A. et al. A novel series of highly potent benzimidazole-based microsomal triglyceride transfer protein inhibitors. J. Med. Chem. 44, 851-856 (2001).
62. Chandler, C. E. et al. CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans. J. Lipid Res. 44, 1887-1901 (2003).
63. Levy, E. The genetic basis of primary disorders of intestinal fat transport. Clin. Invest. Med. 19, 317-324 (1996).
64. Lewis, G. F., Carpenter, A., Adeli, K. & Giacca, A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr. Rev. 23, 201-229 (2002).
65. Shimomura, I. et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear srebp-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 12, 3182-3194 (1998).
66. Moitra J. et al. Life without white fat: a transgenic mouse. Genes Dev. 12, 3168-3181 (1998).
67. Agarwal, A. K. & Garg, A. Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends Endocrinol. Metab. 14, 214-221 (2003).
68. Hanson, R. W. & Reshef, L. Glyceroneogenesis revisited. Biochimie 85, 1199-1205 (2003).
69. Leung, D. W. The structure and functions of human lysophosphatidic acid acyltransferases. Front. Biosci. 6, D944-D953 (2001).
70. Ruan, H. & Pownall, H. J. Overexpression of 1-acyl-glycerol-3-phosphate acyltransferase-α enhances lipid storage in cellular models of adipose tissue and skeletal muscle. Diabetes 50, 233-240 (2001).
71. Cases, S. et al. Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc. Natl Acad. Sci. USA 95, 13018-13023 (1998).
72. Cases, S. et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J. Biol. Chem. 276, 38870-38876 (2001).
73. Ludwig, E. H. et al. DGAT1 promoter polymorphism associated with alterations in body mass index, high density lipoprotein levels and blood pressure in Turkish women. Clin. Genet. 62, 68-73 (2002).
74. Yu, Y. H. et al. Posttranscriptional control of the expression and function of diacylglycerol acyltransferase-1 in mouse adipocytes. J. Biol. Chem. 277, 50876-50884 (2002).
75. Stone, S. J. et al. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J. Biol. Chem. 279, 11767-11776 (2003).
76. Buhman, K. K. et al. DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis. J. Biol. Chem. 277, 25474-25479 (2002).
77. Smith, S. J. et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nature Genet. 25, 87-90 (2000)
78. Chen, H. C., Ladha, Z., Smith, S. J. & Farese, R. V. Jr. Analysis of energy expenditure at different ambient temperatures in mice lacking DGAT1. Am. J. Physiol. Eadocrinol. Metab. 284, E213-E218 (2003).
79. Chen, H. C., Jensen, D. R., Myers, H. M., Eckel, R. H. & Farese, R. V. Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol acyltransferase 1. J. Clin. Invest 111, 1715-1722 (2003).
80. Gibbons, G. F., Islam, K. & Pease, R. J. Mobilisation of triacylglycerol stores. Biochim. Biophys. Acta 1483, 37-57 (2000).
81. Tomoda, H., Namatame, I. & Omura, S. Microbial metabolites with inhibitory activity against lipid metabolism. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 78, 217-240 (2002).
82. Holm, C., Osterlund, T., Laurell, H. & Contreras, J. A. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annu. Rev. Nutr. 20, 365-393 (2000).
83. Sztalryd, C. & Kraemer, F. B. Regulation of hormone-sensitive lipase during fasting. Am. J. Physiol. 266, E179-E185 (1994).
84. Large, V. et al. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J. Lipid Res. 40, 2059-2066 (1999).
85. Garenc, C. et al. The hormone-sensitive lipase gene and body composition: the HERITAGE family study. Int. J. Obes. 26, 220-227 (2002).
86. Lucas, S., Tavernier, G., Tiraby, C., Mairal, A. & Langin, D. Expression of human hormone-sensitive lipase in white adipose tissue of transgenic mice increases lipase activity but does not enhance in vitro lipolysis. J. Lipid Res. 44, 154-163 (2003).
87. Haemmerle, G. et al. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J. Biol. Chem. 277, 4806-4815 (2002).
88. Sekiya, M. et al. Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep(ob/ob) mice. J. Biol. Chem. 279, 15084-15090 (2004).
89. Mulder, H. et al. Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact. J. Biol. Chem. 278, 36380-36388 (2003).
90. Osuga, J. et al. Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc. Natl Acad. Sci. USA 97, 787-792 (2000).
91. Wei, Y. et al. Crystal structure of brefeldin A esterase, a bacterial homolog of the mammalian hormone-sensitive lipase. Nature Struct. Biol. 6, 340-345 (1999).
92. Tansey, J. T. et al. Functional studies on native and mutated forms of perilipins: a role in protein kinase A-mediated lipolysis of triacylglycerols in Chinese hamster ovary cells. J. Biol. Chem. 278, 8401-8406 (2003).
93. Miura, S. et al. Functional conservation for lipid storage droplet association among Perilipin, ADRP, and TIP47 (PAT)-related proteins in mammals, Drosophila, and Dictyostelium. J. Biol. Chem. 277, 32253-32257 (2002).
94. Tansey, J. T. et al. Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc. Natl Acad. Sci. USA 98, 6494-6499 (2001).
95. Martinez-Botas, J. et al. Absence of perilipin results in leanness and reverses obesity in Lepr (db/db) mice. Nature Genet. 26, 474-479 (2000).
96. Castro-Chavez, F. et al. Coordinated upregulation of oxidative pathways and downregulation of lipid biosynthesis underlie obesity resistance in perilipin knockout mice: a microarray gene expression profile. Diabetes 52, 2666-2674 (2003).
97. Sul, H. S. & Wang, D. Nutritional and hormonal regulation of enzymes in fat synthesis - studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu. Rev. Nutr. 18, 331-351 (1998).
98. Park, H. et al. Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J. Biol. Chem. 277, 32571-32577 (2002).
99. Zhou, Y. T., Wang, Z. W., Higa, M., Newgard, C. B. & Unger, R. H. Reversing adipocyte differentiation: implications for treatment of obesity. Proc. Natl Acad. Sci. USA 96, 2391-2395 (1999).
100. Dircks, L. K. & Sul, H. S. Mammalian mitochondrial glycerol-3-phosphate acyltransferase. Biochim. Biophys. Acta 1348, 17-26 (1997).
101. Igal, R. A., Wang, S. L., Gonzalez-Baro, M. & Coleman, R. A. Mitochondrial glycerol phosphate acyltransferase directs the incorporation of exogenous fatty acids into triacylglycerol. J. Biol. Chem. 276, 42205-42212 (2001).
102. Hammond, L. E. et al. Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition. Mol. Cell. Biol. 22, 8204-8214 (2002).
103. Smith, S., Witkowski, A. & Joshi, A. K. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res. 42, 289-317 (2003).
104. Jayakumar, A. et al. Human fatty acid synthase: properties and molecular cloning. Proc. Natl Acad. Sci. USA 92, 8695-8699 (1995).
105. Kuhajda, F. P. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16, 202-208 (2000).
106. Kuhajda, F. P. et al. Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc. Natl Acad. Sci. USA 97, 3450-3454 (2000).
107. Loftus, T. M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379-2381 (2000).
108. Shimokawa, T., Kumar, M. V. & Lane, M. D. Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc. Natl Acad. Sci. USA 99, 66-71 (2002).
109. Hu, Z. Y., Cha, S. H., Chohnan, S. & Lane, M. D. Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc. Natl Acad. Sci. USA 100, 12624-12629 (2003).
110. Takahashi, K. A., Smart, J. L., Liu, H. & Cone, R. D. The anorexigenic fatty acid synthase inhibitor, C75, is a non-specific neuronal activator. Endocrinology 25, 25 (2003).
111. Schlesinger, M. J. & Malfer, C. Cerulenin blocks fatty acid acylation of glycoproteins and inhibits vesicular stomatitis and Sindbis virus particle formation. J. Biol. Chem. 257, 9887-9890 (1982).
112. Lawrence, D. S., Zilfou, J. T. & Smith, C. D. Structure-activity studies of cerulenin analogues as protein palmiloylation inhibitors. J. Med. Chem. 42, 4932-4941 (1999).
113. Thupari, J. N., Pinn, M. L. & Kuhajda, F. P. Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. Biochem. Biophys. Res. Comm. 285, 217-223 (2001).
114. Thupari, J. N., Landree, L. E., Ronnett, G. V. & Kuhajda, F. P. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. Proc. Natl Acad. Sci. USA 99, 9498-9502 (2002).
115. Chirala, S. S. et al. Fatty acid synthesis is essential in embryonic development: fatty acid synthase null mutants and most of the heterozygotes die in utero. Proc. Natl Acad. Sci. USA 100, 6358-6363 (2003).
116. Metzger, D., Clifford, J., Chiba, H. & Chambon, P. Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. Proc. Natl Acad. Sci. USA 92, 6991-6995 (1995).
117. van der Leij, F. R., Huijkman, N. C. A., Boomsma, C., Kuipers, J. R. G. & Bartelds, B. Genomics of the human carnitine acyltransferase genes. Mol. Genet. Metab. 71, 139-153 (2000).
118. McGarry, J. D. & Brown, N. F. The mitochondrial carnitine palmitoyltransferase system - from concept to molecular analysis. Eur. J. Biochem. 244, 1-14 (1997).
119. Awan, M. M. & Saggerson, E. D. Malonyl-CoA metabolism in cardiac myocytes and its relevance to the control of fatty acid oxidation. Biochem. J. 295, 61-66 (1993).
120. Hamilton, C. & Saggerson, E. D. Malonyl-CoA metabolism in cardiac myocytes. Biochem. J. 350, 61-67 (2000).
121. Saddik, M., Gamble, J., Witters, L. A. & Lopaschulk, G. D. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J. Biol. Chem. 268, 25836-25845 (1993).
122. Ruderman, N. B., Saha, A. K., Vavvas, D. & Witters, L. A. Malonyl-CoA, fuel sensing, and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 39, E1-E18 (1999).
123. Winder, W. W. Malonyl-CoA: regulator of fatty acid oxidation in muscle during exercise. Exerc. Sport Sci. Rev. 26, 117-132 (1998).
124. An, J. et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nature Med. 10, 268-274 (2004).
125. Kim, J. Y., Hickner R. C., Cortright, R. L., Dohm, G. L. & Houmard, J. A. Lipid oxidation is reduced in obese human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 279, E1039-E1044 (2000).
126. Dobbins, R. L. et al. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 50, 123-130 (2001).
127. Sacksteder, K. A., Morrell, J. C., Wanders, R. J., Matalon, R. & Gould, S. J. MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency. J. Biol. Chem. 274, 24461-24468 (1999).
128. Gobin, S. et al. Functional and structural basis of carnitine palmitoyltransferase 1A deficiency. J. Biol. Chem. 278, 50428-50434 (2003).
129. Thuillier, L. et al. Correlation between genotype, metabolic data, and clinical presentation in carnitine palmitoyltransferase 2 (CPT2) deficiency. Hum. Mutat. 21, 493-501 (2003).
130. Lahjouji, K., Mitchell, G. A. & Qureshi, I. A. Carnitine transport by organic cation transporters and systemic carnitine deficiency. Mol. Genet. Metab. 73, 287-297 (2001).
131. Jackson, V. N., Zammit, V. A. & Price, N. T. Identification of positive and negative determinants of malonyl-CoA sensitivity and carnitine affinity within the amino termini of rat liver- and muscle-type carnitine palmitoyltransferase I. J. Biol. Chem. 275, 38410-38416 (2000).
132. Morillas, M. et al. Identification of conserved amino acid residues in rat liver carnitine palmitoyltransferase I critical for malonyl-CoA inhibition: mutation of methionine 593 abolishes malonyl-CoA inhibition. J. Biol. Chem. 278, 9058-9063 (2003).
133. Shi, J. Y., Zhu, H. F., Arvidson, D. N. & Woldegiorgis, G. A single amino acid change (substitution of glutamate 3 with alanine) in the N-terminal region of rat liver carnitine palmitoyltransferase I abolishes malonyl-CoA inhibition and high affinity binding. J. Biol. Chem. 274, 9421-9426 (1999).
134. Zhu, H. et al. Substitution of glutamate-3, valine-19, leucine-23, and serine-24 with alanine in the N-terminal region of human heart muscle carnitine palmitoyltransferase I abolishes malonyl CoA inhibition and binding. Arch. Biochem. Biophys. 413, 67-74 (2003).
135. Jogl, G. & Tong, L. Crystal structure of carnitine acetyltransferase and implications for the catalytic mechanism and fatty acid transport. Cell 112, 113-122 (2003).
136. Anderson, R. C. Carnitine palmitoyltransferase: a viable target for the treatment of NIDDM? Curr. Pharm. Des. 4, 1-16 (1998).
137. Giannessi, F. et al. Discovery of a long-chain carbamoyl aminocarnitine derivative, a reversible carnitine palmitoyltransferase inhibitor with antiketotic and antidiabetic activity. J. Med. Chem. 46, 303-309 (2003).
138. Abu-Elheiga, L, Matzuk, M. M., Abo-Hashema, K. A. & Wakil, S. J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291, 2613-2616 (2001).
139. Kashfi, K. & Cook, G. A. Topology of hepatic mitochondrial carnitine palmitoyltransferase I. Adv. Exp. Med. Biol. 466, 27-42 (1999).
140. Abu-Elheiga, L., Almarza-Ortega, D. B., Baldini, A. & Wakil, S. J. Human acetyl-CoA carboxylase 2. Molecular cloning, characterization, chromosomal mapping, and evidence for two isoforms. J. Biol. Chem. 272, 10669-10677 (1997).
141. Abu-Elheiga, L. et al. The subcellular localization of acetyl-CoA carboxylase 2. Proc. Natl Acad. Sci. USA 97, 1444-1449 (2000).
142. Zhang, L., Joshi, A. K. & Smith, S. Cloning, expression, characterization, and interaction of two components of a human mitochondrial fatty acid synthase. Malonyl-transferase and acyl carrier protein. J. Biol. Chem. 278, 40067-40074 (2003).
143. Hardie, D. G. & Pan, D. A. Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase. Biochem. Soc. Trans. 30, 1064-1070 (2002).
144. Munday, M. R. Regulation of mammalian acetyl-CoA carboxylase. Biochem. Soc. Trans. 30, 1059-1064 (2002).
145. Kudo, N., Barr, A. J., Barr, R. L., Desai, S. & Lopaschuk, G. D. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J. Biol. Chem. 270, 17513-17520 (1995).
146. Winder, W. W. & Hardie, D. G. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise, Am. J. Physiol. 270, E299-E304 (1996).
147. Hopkins, T. A., Dyck, J. R. B. & Lopaschuk, G. D. AMP-activated protein kinase regulation of fatty acid oxidation in the ischaemic heart. Biochem. Soc. Trans. 31, 207-212 (2003).
148. Kaushik, V. K. et al. Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR. Am. J. Physiol. Endocrinol. Metab. 281, E335-E340 (2001).
149. Abu-Elheiga, L., Oh, W., Kordari, P. & Wakil, S. J. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc. Natl Acad. Sci. USA 100, 10207-10212 (2003).
150. Gronwald, J. W. Herbicides inhibiting acetyl-CoA carboxylase. Biochem. Soc. Trans. 22, 616-621 (1994).
151. Seng, T. W., Skillman, T. R., Yang, N. Y. & Hammond, C. Cyclohexanedione herbicides are inhibitors of rat heart acetyl-CoA carboxylase. Bioorg. Med. Chem. Lett. 13, 3237-3242 (2003).
152. Arbeeny, C. M., Meyers, D. S., Bergquist, K. E. & Gregg, R. E. Inhibition of fatty acid synthesis decreases very low density lipoprotein secretion in the hamster. J. Lipid Res. 33, 843-851 (1992).
153. Harwood, H. J. Jr. et al. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J. Biol. Chem. 278, 37099-37111 (2003).
154. Zhang, H., Yang, Z., Shen, Y. & Tong, L. Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase. Science 299, 2064-2067 (2003).
155. Ntambi, J. M. & Miyazaki, M. Recent insights into stearoyl-CoA desaturase-1. Curr. Opin. Lipidol. 14, 255-261 (2003).
156. Miyazaki, M., Man, W. C. & Ntambi, J. M. Targeted disruption of stearoyl-CoA desaturase1 gene in mice causes atrophy of sebaceous and meibomian glands and depletion of wax esters in the eyelid. J. Nutr. 131, 2260-2268 (2001).
157. Cohen, P. et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297, 240-243 (2002).
158. Ntambi, J. M. et al. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc. Natl Acad. Sci. USA 99, 11482-11486 (2002).
159. Volpe, J. J. & Vagelos, P. R. Mechanisms and regulation of biosynthesis of saturated fatty acids. Physiol. Rev. 56, 339-417 (1976).
160. Ntambi, J. M. & Bene, H. Polyunsaturated fatty acid regulation of gene expression. J. Mol. Neurosci. 16, 273-278; discussion 279-284 (2001).
161. Miyazaki, M., Kim, Y. C. & Ntambi, J. M. A lipogenic diet in mice with a disruption of the stearoy-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis. J. Lipid Res. 42, 1018-1024 (2001).
162. Obici, S., Feng, Z. H., Anduini, A., Conti, R. & Rossetti, L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nature Med. 9, 756-761 (2003).
163. Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268-272 (2003).