A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics

EBioMedicine

Volumn 8, Issue , 2016, Pages 49-59

  Tschapalda, Kirsten ^a,b,c   Zhang, Ya Qin ^d   Liu, Li ^d   Golovnina, Kseniya ^e   Schlemper, Thomas ^a   Eichmann, Thomas O ^f   Lal Nag, Madhu ^d   Sreenivasan, Urmila ^g   McLenithan, John ^g   Ziegler, Slava ^b   Sztalryd, Carole ^g,h   Lass, Achim ^f   Auld, Douglas ^d,i   Oliver, Brian ^e   Waldmann, Herbert ^b   Li, Zhuyin ^d,j   Shen, Min ^d   Boxer, Matthew B ^d   Beller, Mathias ^a  

^a HEINRICH HEINE UNIVERSITY   (Germany)

^b MAX PLANCK INSTITUTE OF MOLECULAR PHYSIOLOGY   (Germany)

^c MAX PLANCK INSTITUTE FOR BIOPHYSICAL CHEMISTRY   (Germany)

^d NATIONAL INSTITUTES OF HEALTH   (United States)

^e NATIONAL INSTITUTES OF HEALTH   (United States)

^f UNIVERSITY OF GRAZ   (Austria)

^g UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^h BALTIMORE VA MEDICAL CENTER   (United States)

ⁱ NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^j BRISTOL MYERS SQUIBB   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

DIACYLGLYCEROL ACYLTRANSFERASE 1; DIACYLGLYCEROL ACYLTRANSFERASE; ENZYME INHIBITOR; FATTY ACID; MOLECULAR LIBRARY; PYRROLE DERIVATIVE; THIENOPYRROLE;

ANIMAL CELL; ARTICLE; CELL VIABILITY; CONTROLLED STUDY; DROSOPHILA; DRUG SCREENING; EPISTASIS; FATTY ACID OXIDATION; FATTY ACID TRANSPORT; FEMALE; FLUORESCENCE MICROSCOPY; GENE EXPRESSION PROFILING; LIPID METABOLISM; LIPOGENESIS; MALE; NONHUMAN; PRIORITY JOURNAL; RNA SEQUENCE; STRUCTURE ACTIVITY RELATION; UPREGULATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL DIFFERENTIATION; CELL LINE; CHEMISTRY; CHLOROCEBUS AETHIOPS; COS CELL LINE; DRUG EFFECTS; GENETICS; GENOMICS; HUMAN; LIPID PEROXIDATION; METABOLISM; MOLECULAR LIBRARY; MOUSE; PHARMACOLOGY; PHENOTYPE; SEQUENCE ANALYSIS;

ANIMALS; CELL DIFFERENTIATION; CELL LINE; CERCOPITHECUS AETHIOPS; COS CELLS; DIACYLGLYCEROL O-ACYLTRANSFERASE; DROSOPHILA; ENZYME INHIBITORS; EPISTASIS, GENETIC; FATTY ACIDS; FEMALE; GENOMICS; HUMANS; LIPID PEROXIDATION; MALE; MICE; PHENOTYPE; PYRROLES; SEQUENCE ANALYSIS, RNA; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84969919730     PISSN: None     EISSN: 23523964     Source Type: Journal    
DOI: 10.1016/j.ebiom.2016.04.014     Document Type: Article

References (70)

1. Anandhakumar C., Kizaki S., Bando T., Pandian G., Sugiyama H. Advancing small-molecule-based chemical biology with next-generation sequencing technologies. Chembiochem 2015, 16:20-38.
2. Baker K., Thummel C. Diabetic larvae and obese flies-emerging studies of metabolism in drosophila. Cell Metab. 2007, 6:257-266.
3. Beller M., Bulankina A.V., Hsiao H.-H.H., Urlaub H., Jäckle H., Kühnlein R.P. PERILIPIN-dependent control of lipid droplet structure and fat storage in drosophila. Cell Metab. 2010, 12:521-532.
4. Bi J., Xiang Y., Chen H., Liu Z., Grönke S., Kühnlein R.P., Huang X. Opposite and redundant roles of the two drosophila perilipins in lipid mobilization. J. Cell Sci. 2012, 125:3568-3577.
5. Birch A.M., Buckett L.K., Turnbull A.V. DGAT1 inhibitors as anti-obesity and anti-diabetic agents. Curr. Opin. Drug Discov. Dev. 2010, 13:489-496.
6. Böhni R., Riesgo-Escovar J., Oldham S., Brogiolo W., Stocker H., Andruss B.F., Beckingham K., Hafen E. Autonomous control of cell and organ size by CHICO, a drosophila homolog of vertebrate IRS1-4. Cell 1999, 97:865-875.
7. Boulant S., Douglas M., Moody L., Budkowska A., Targett-Adams P., McLauchlan J. Hepatitis C virus Core protein induces lipid droplet redistribution in a microtubule- and dynein-dependent manner. Traffic 2008, 9:1268-1282.
8. Buszczak M., Lu X., Segraves W.A., Chang T.Y., Cooley L. Mutations in the midway gene disrupt a drosophila acyl coenzyme a: diacylglycerol acyltransferase. Genetics 2002, 160:1511-1518.
9. Cai L., Sutter B.M., Li B., Tu B.P. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol. Cell 2011, 42:426-437.
10. Carone B., Fauquier L., Habib N., Shea J., Hart C., Li R., Bock C., Li C., Gu H., Zamore P., et al. Paternally induced transgenerational environmental reprogramming of metabolic Gene expression in mammals. Cell 2010, 143:1084-1096.
11. Carvalho M., Schwudke D., Sampaio J.L., Palm W., Riezman I., Dey G., Gupta G.D., Mayor S., Riezman H., Shevchenko A., et al. Survival strategies of a sterol auxotroph. Development 2010, 137:3675-3685.
12. Choi H.J., Hwang S., Lee S.-H.H., Lee Y.R., Shin J., Park K.S., Cho Y.M. Genome-wide identification of palmitate-regulated immediate early genes and target genes in pancreatic beta-cells reveals a central role of NF-κB. Mol. Biol. Rep. 2012, 39:6781-6789.
13. De Gottardi A., Vinciguerra M., Sgroi A., Moukil M., Ravier-Dall'Antonia F., Pazienza V., Pugnale P., Foti M., Hadengue A. Microarray analyses and molecular profiling of steatosis induction in immortalized human hepatocytes. Lab. Investig. 2007, 87:792-806.
14. De Nadal E., Ammerer G., Posas F. Controlling gene expression in response to stress. Nat. Rev. Genet. 2011, 12:833-845.
15. Devita R., Pinto S. Current status of the Research and Development of diacylglycerol O-acyltransferase 1 (DGAT1) inhibitors. J. Med. Chem. 2013, 56:9820-9825.
16. Eder J., Sedrani R., Wiesmann C. The discovery of first-in-class drugs: origins and evolution. Nat. Rev. Drug Discov. 2014, 13:577-587.
17. Farese R.V., Walther T.C. Lipid droplets finally get a little R-E-S-P-E-C-T. Cell 2009, 139:855-860.
18. Farooqi I.S., O'Rahilly S. Genetic factors in human obesity. Obes. Rev. 2007, 8(Suppl. 1):37-40.
19. Gonsalves F.C., Klein K., Carson B.B., Katz S., Ekas L.A., Evans S., Nagourney R., Cardozo T., Brown A.M., DasGupta R. An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:5954-5963.
20. Grönke S., Beller M., Fellert S., Ramakrishnan H., Jäckle H., Kühnlein R.P. Control of fat storage by a drosophila PAT domain protein. Curr. Biol. 2003, 13:603-606.
21. Grönke S., Mildner A., Fellert S., Tennagels N., Petry S., Müller G., Jäckle H., Kühnlein R.P. Brummer lipase is an evolutionary conserved fat storage regulator in drosophila. Cell Metab. 2005, 1:323-330.
22. Grönke S., Müller G., Hirsch J., Fellert S., Andreou A., Haase T., Jäckle H., Kühnlein R.P. Dual lipolytic control of body fat storage and mobilization in drosophila. PLoS Biol. 2007, 5.
23. Gross D., Silver D. Cytosolic lipid droplets: from mechanisms of fat storage to disease. Crit. Rev. Biochem. Mol. Biol. 2014, 49:304-326.
24. Guan W., Steffen B.T., Lemaitre R.N., Wu J.H., Tanaka T., Manichaikul A., Foy M., Rich S.S., Wang L., Nettleton J.A., et al. Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. Circ. Cardiovasc. Genet. 2014, 7:321-331.
25. Haemmerle G., Zimmermann R., Hayn M., Theussl C., Waeg G., Wagner E., Sattler W., Magin T., Wagner E., Zechner R. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J. Biol. Chem. 2002, 277:4806-4815.
26. Haemmerle G., Lass A., Zimmermann R., Gorkiewicz G., Meyer C., Rozman J., Maier R., Theussl C., Eder S., Kratky D., et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 2006, 312:734-737.
27. Harris C.A., Haas J.T., Streeper R.S., Stone S.J., Kumari M., Yang K., Han X., Brownell N., Gross R.W., Zechner R., et al. DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. J. Lipid Res. 2011, 52:657-667.
28. Hildebrandt A., Bickmeyer I., Kühnlein R. Reliable drosophila body fat quantification by a coupled colorimetric assay. PLoS One 2011, 6.
29. Huang R., Southall N., Wang Y., Yasgar A., Shinn P., Jadhav A., Nguyen D.-T., Austin C. The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci. Transl. Med. 2011, 3:80ps16.
30. Igal R.A., Wang P., Coleman R.A. Triacsin C blocks de novo synthesis of glycerolipids and cholesterol esters but not recycling of fatty acid into phospholipid: evidence for functionally separate pools of acyl-CoA. Biochem. J. 1997, 324(Pt 2):529-534.
31. Inglese J., Auld D., Jadhav A., Johnson R., Simeonov A., Yasgar A., Zheng W., Austin C. Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc. Natl. Acad. Sci. U. S. A. 2006, 103:11473-11478.
32. Kamentsky L., Jones T.R., Fraser A., Bray M.-A.A., Logan D.J., Madden K.L., Ljosa V., Rueden C., Eliceiri K.W., Carpenter A.E. Improved structure, function and compatibility for CellProfiler: modular high-throughput image analysis software. Bioinformatics 2011, 27:1179-1180.
33. Kühnlein R.P. The contribution of the drosophila model to lipid droplet research. Prog. Lipid Res. 2011, 50:348-356.
34. Kumar Y., Cocchiaro J., Valdivia R. The obligate intracellular pathogen chlamydia trachomatis targets host lipid droplets. Curr. Biol. 2006, 16:16461651.
35. Lass A., Zimmermann R., Oberer M., Zechner R. Lipolysis - a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Prog. Lipid Res. 2011, 50:14-27.
36. Lehnert K., Ward H., Berry S.D., Ankersmit-Udy A., Burrett A., Beattie E.M., Thomas N.L., Harris B., Ford C.A., Browning S.R., et al. Phenotypic population screen identifies a new mutation in bovine DGAT1 responsible for unsaturated milk fat. Sci. Rep. 2015, 5:8484.
37. Listenberger L.L., Han X., Lewis S.E., Cases S., Farese R.V., Ory D.S., Schaffer J.E. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci. U. S. A. 2003, 100:3077-3082.
38. Liu L., Yu S., Khan R., Ables G., Bharadwaj K., Hu Y., Huggins L., Eriksson J., Buckett L., Turnbull A., et al. DGAT1 deficiency decreases PPAR expression and does not lead to lipotoxicity in cardiac and skeletal muscle. J. Lipid Res. 2011, 52:732-744.
39. Liu L., Zhang K., Sandoval H., Yamamoto S., Jaiswal M., Sanz E., Li Z., Hui J., Graham B.H., Quintana A., et al. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell 2015, 160:177-190.
40. Lusis A., Attie A., Reue K. Metabolic syndrome: from epidemiology to systems biology. Nat. Rev. Genet. 2008, 9:819-830.
41. Matsuda D., Tomoda H. DGAT inhibitors for obesity. Curr. Opin. Investig. Drugs 2007, 8:836-841.
42. Murphy The biogenesis and functions of lipid bodies in animals, plants and microorganisms. Prog. Lipid Res. 2001, 40:325-438.
43. Pandey U., Nichols C. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol. Rev. 2011, 63:411-436.
44. Perrimon N., Friedman A., Mathey-Prevot B., Eggert U.S. Drug-target identification in drosophila cells: combining high-throughout RNAi and small-molecule screens. Drug Discov. Today 2007, 12:28-33.
45. Pierre S., Ponting L., Stefancsik R., McQuilton P., Consortium, F. FlyBase 102-advanced approaches to interrogating FlyBase. Nucleic Acids Res. 2014, 42:D780-D788.
46. Rajan A., Perrimon N. Drosophila as a model for Interorgan communication: lessons from studies on energy homeostasis. Dev. Cell 2011, 21:29-31.
47. Rajan A., Perrimon N. Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell 2012, 151:123-137.
48. Rial E., Rodríguez-Sánchez L., Gallardo-Vara E., Zaragoza P., Moyano E., González-Barroso M. Lipotoxicity, fatty acid uncoupling and mitochondrial carrier function. Biochim. Biophys. Acta Biomembr. 2010, 1797:800-806.
49. Sattar N., Gill J. Type 2 diabetes as a disease of ectopic fat?. BMC Med. 2014, 12:123.
50. Schober G., Arnold M., Birtles S., Buckett L.K., Pacheco-López G., Turnbull A.V., Langhans W., Mansouri A. Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats. J. Lipid Res. 2013, 54:1369-1384.
51. Shen L.R., Lai C.Q., Feng X., Parnell L.D., Wan J.B., Wang J.D., Li D., Ordovas J.M., Kang J.X. Drosophila lacks C20 and C22 PUFAs. J. Lipid Res. 2010, 51:2985-2992.
52. Shirazi F., Farmakiotis D., Yan Y., Albert N., Kim-Anh D., Kontoyiannis D. Diet modification and metformin have a beneficial effect in a fly model of obesity and mucormycosis. PLoS One 2014, 9.
53. Shulman G. Ectopic fat in insulin resistance, dyslipidemia, and Cardiometabolic disease. N. Engl. J. Med. 2014, 371:1131-1141.
54. Smith, Cases, Jensen, Chen, Sande, Tow, Sanan, Raber, Eckel, Farese Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat. Genet. 2000, 25:87-90.
55. Stone S.J., Myers H.M., Watkins S.M., Brown B.E., Feingold K.R., Elias P.M., Farese R.V. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J. Biol. Chem. 2004, 279:11767-11776.
56. Sullivan E.L., Grove K.L. Metabolic imprinting in obesity. Front. Eat. Weight Regul. 2009, 63:186-194.
57. Takahashi H., McCaffery J.M., Irizarry R.A., Boeke J.D. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol. Cell 2006, 23:207-217.
58. Tian Y., Bi J., Shui G., Liu Z., Xiang Y., Liu Y., Wenk M., Yang H., Huang X. Tissue-autonomous function of drosophila Seipin in preventing ectopic lipid droplet formation. PLoS Genet. 2011, 7. e1001364.
59. Turnbaugh P., Ley R., Mahowald M., Magrini V., Mardis E., Gordon J. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006, 444:1027-1131.
60. Vendrell-Navarro G., Brockmeyer A., Waldmann H., Janning P., Ziegler S. Identification of the targets of biologically active small molecules using quantitative proteomics. Methods Mol. Biol. 2015, 1263:263-286.
61. Villanueva C.J., Monetti M., Shih M., Zhou P., Watkins S.M., Bhanot S., Farese R.V. Specific role for acyl CoA:diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids. Hepatology 2009, 50:434-442.
62. Wang H., Hu L., Dalen K., Dorward H., Marcinkiewicz A., Russell D., Gong D., Londos C., Yamaguchi T., Holm C., et al. Activation of hormone-sensitive lipase requires two steps, protein phosphorylation and binding to the PAT-1 domain of lipid droplet coat proteins. J. Biol. Chem. 2009, 284:32116-32125.
63. Wang H., Bell M., Sreenivasan U., Sreenevasan U., Hu H., Liu J., Dalen K., Londos C., Yamaguchi T., Rizzo M.A., et al. Unique regulation of adipose triglyceride lipase (ATGL) by perilipin 5, a lipid droplet-associated protein. J. Biol. Chem. 2011, 286:15707-15715.
64. Weiss W., Taylor S., Shokat K. Recognizing and exploiting differences between RNAi and small-molecule inhibitors. Nat. Chem. Biol. 2007, 3:739-744.
65. Wellen K.E., Hatzivassiliou G., Sachdeva U.M., Bui T.V., Cross J.R., Thompson C.B. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009, 324:1076-1080.
66. Wilfling F., Wang H., Haas J., Krahmer N., Gould T., Uchida A., Cheng J.-X., Graham M., Christiano R., Fröhlich F., et al. Triacylglycerol synthesis enzymes mediate lipid droplet growth by Relocalizing from the ER to lipid droplets. Dev. Cell 2013, 24:384-399.
67. Willer C.J., Schmidt E.M., Sengupta S., Peloso G.M., Gustafsson S., Kanoni S., Ganna A., Chen J., Buchkovich M.L., Mora S., et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 2013, 45:1274-1283.
68. Winter G.E., Rix U., Lissat A., Stukalov A., Müllner M.K., Bennett K.L., Colinge J., Nijman S.M., Kubicek S., Kovar H., et al. An integrated chemical biology approach identifies specific vulnerability of Ewing's sarcoma to combined inhibition of aurora kinases a and B. Mol. Cancer Ther. 2011, 10:1846-1856.
69. Zámbó V., Simon-Szabó L., Szelényi P., Kereszturi E., Bánhegyi G., Csala M. Lipotoxicity in the liver. World J. Hepatol. 2013, 5:550-557.
70. Ziegler S., Pries V., Hedberg C., Waldmann H. Target identification for small bioactive molecules: finding the needle in the haystack. Angew. Chem. Int. Ed. Eng. 2013, 52:2744-2792.