title: Modeling the mechanism of action of a DGAT1 inhibitor using a causal reasoning platform.
abstract: Triglyceride accumulation is associated with obesity and type 2 diabetes. Genetic disruption of diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the final reaction of triglyceride synthesis, confers dramatic resistance to high-fat diet induced obesity. Hence, DGAT1 is considered a potential therapeutic target for treating obesity and related metabolic disorders. However, the molecular events shaping the mechanism of action of DGAT1 pharmacological inhibition have not been fully explored yet. Here, we investigate the metabolic molecular mechanisms induced in response to pharmacological inhibition of DGAT1 using a recently developed computational systems biology approach, the Causal Reasoning Engine (CRE). The CRE algorithm utilizes microarray transcriptomic data and causal statements derived from the biomedical literature to infer upstream molecular events driving these transcriptional changes. The inferred upstream events (also called hypotheses) are aggregated into biological models using a set of analytical tools that allow for evaluation and integration of the hypotheses in context of their supporting evidence. In comparison to gene ontology enrichment analysis which pointed to high-level changes in metabolic processes, the CRE results provide detailed molecular hypotheses to explain the measured transcriptional changes. CRE analysis of gene expression changes in high fat habituated rats treated with a potent and selective DGAT1 inhibitor demonstrate that the majority of transcriptomic changes support a metabolic network indicative of reversal of high fat diet effects that includes a number of molecular hypotheses such as PPARG, HNF4A and SREBPs. Finally, the CRE-generated molecular hypotheses from DGAT1 inhibitor treated rats were found to capture the major molecular characteristics of DGAT1 deficient mice, supporting a phenotype of decreased lipid and increased insulin sensitivity.
authors.affiliation: Compound Safety Prediction Group, Pfizer Inc, Groton, Connecticut, United States of America. Ahmed.Enayetallah@pfizer.com
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Enayetallah
authors.forename: Daniel
authors.initials: D
authors.lastname: Ziemek
authors.forename: Michael T
authors.initials: MT
authors.lastname: Leininger
authors.forename: Ranjit
authors.initials: R
authors.lastname: Randhawa
authors.forename: Jianxin
authors.initials: J
authors.lastname: Yang
authors.forename: Tara B
authors.initials: TB
authors.lastname: Manion
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Mather
authors.forename: William J
authors.initials: WJ
authors.lastname: Zavadoski
authors.forename: Max
authors.initials: M
authors.lastname: Kuhn
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: Shelly Ann G
authors.initials: SA
authors.lastname: des Etages
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gibbs
authors.forename: Nigel
authors.initials: N
authors.lastname: Greene
authors.forename: Claire M
authors.initials: CM
authors.lastname: Steppan
mesh_terms: D000465:Algorithms; D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005247:Feeding Behavior; D008962:Models, Theoretical; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood
chemical_list: D004791:Enzyme Inhibitors; D014280:Triglycerides; C494883:Dgat1 protein, rat; D051048:Diacylglycerol O-Acyltransferase
references.citation: J Clin Invest. 2002 Apr;109(8):1049-55
references.pmid: 11956242
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13018-23
references.pmid: 9789033
references.citation: Lancet. 2005 Oct 1;366(9492):1197-209
references.pmid: 16198769
references.citation: Mol Biol Cell. 2007 Sep;18(9):3388-97
references.pmid: 17581860
references.citation: J Atheroscler Thromb. 2009 Mar;16(1):6-11
references.pmid: 19262004
references.citation: Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):482-6
references.pmid: 15569818
references.citation: Gene. 2006 Mar 15;369:90-9
references.pmid: 16380219
references.citation: BMC Bioinformatics. 2009 Feb 03;10:47
references.pmid: 19192285
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Jun;286(6):G1032-41
references.pmid: 14739145
references.citation: Curr Opin Clin Nutr Metab Care. 2011 Mar;14(2):115-20
references.pmid: 21178610
references.citation: J Lipid Res. 2010 Jul;51(7):1770-80
references.pmid: 20147738
references.citation: Stat Appl Genet Mol Biol. 2004;3:Article3
references.pmid: 16646809
references.citation: Diabetes Technol Ther. 2005 Apr;7(2):323-36
references.pmid: 15857235
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G27-38
references.pmid: 17947452
references.citation: Atheroscler Suppl. 2008 Sep;9(2):7-13
references.pmid: 18653387
references.citation: Biostatistics. 2006 Apr;7(2):198-212
references.pmid: 16135694
references.citation: Endocrinology. 2002 Aug;143(8):2893-8
references.pmid: 12130553
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G782-92
references.pmid: 19196952
references.citation: J Mol Endocrinol. 2004 Feb;32(1):195-208
references.pmid: 14766002
references.citation: J Biol Chem. 2003 Feb 28;278(9):7674-82
references.pmid: 12482874
references.citation: J Biol Chem. 2005 Feb 11;280(6):4959-67
references.pmid: 15537655
references.citation: J Biol Chem. 2004 Mar 19;279(12):11767-76
references.pmid: 14668353
references.citation: Mol Cell Biol. 2002 Apr;22(8):2607-19
references.pmid: 11909955
references.citation: ACS Med Chem Lett. 2011 Mar 18;2(5):407-12
references.pmid: 24900321
references.citation: J Biol Chem. 2003 Nov 21;278(47):47232-9
references.pmid: 14500732
references.citation: Biochem Pharmacol. 2002 Sep;64(5-6):893-901
references.pmid: 12213584
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D5-16
references.pmid: 19910364
references.citation: J Lipid Res. 2011 Apr;52(4):732-44
references.pmid: 21205704
references.citation: J Biol Chem. 2001 Oct 19;276(42):38870-6
references.pmid: 11481335
references.citation: Bioinformatics. 2012 Apr 15;28(8):1114-21
references.pmid: 22355083
references.citation: Genome Res. 2003 Nov;13(11):2498-504
references.pmid: 14597658
references.citation: Cell. 2005 Jan 28;120(2):261-73
references.pmid: 15680331
references.citation: Genomics. 2003 Feb;81(2):98-104
references.pmid: 12620386
references.citation: Endocrinology. 2001 Mar;142(3):1269-77
references.pmid: 11181544
references.citation: J Biol Chem. 2003 Jan 3;278(1):498-505
references.pmid: 12401792
references.citation: J Biol Chem. 2008 Oct 31;283(44):29802-11
references.pmid: 18768481