title: An integrated reverse functional genomic and metabolic approach to understanding orotic acid-induced fatty liver.
abstract: In functional genomics, DNA microarrays for gene expression profiling are increasingly being used to provide insights into biological function or pathology. To better understand the significance of the multiple transcriptional changes across a time period, the temporal changes in phenotype must be described. Orotic acid-induced fatty liver disease was investigated at the transcriptional and metabolic levels using microarrays and metabolic profiling in two strains of rats. High-resolution 1H-NMR spectroscopic analysis of liver tissue indicated that Kyoto rats compared with Wistar rats are predisposed to the insult. Metabolite analysis and gene expression profiling following orotic acid treatment identified perturbed metabolic pathways, including those involved in fatty acid, triglyceride, and phospholipid synthesis, beta-oxidation, altered nucleotide, methyl donor, and carbohydrate metabolism, and stress responses. Multivariate analysis and statistical bootstrapping were used to investigate co-responses with transcripts involved in metabolism and stress responses. This reverse functional genomic strategy highlighted the relationship between changes in the transcription of stearoyl-CoA desaturase 1 and those of other lipid-related transcripts with changes in NMR-derived lipid profiles. The results suggest that the integration of 1H-NMR and gene expression data sets represents a robust method for identifying a focused line of research in a complex system.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom. jlg40@mole.bio.cam.ac.uk
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Bonney
authors.forename: Chris
authors.initials: C
authors.lastname: Mann
authors.forename: Abdul M
authors.initials: AM
authors.lastname: Hebbachi
authors.forename: Geoff F
authors.initials: GF
authors.lastname: Gibbons
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: Carol C
authors.initials: CC
authors.lastname: Shoulders
authors.forename: James
authors.initials: J
authors.lastname: Scott
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D023281:Genomics; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D020411:Oligonucleotide Array Sequence Analysis; D009963:Orotic Acid / Q000008:administration & dosage; D010641:Phenotype; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D012333:RNA, Messenger; D009963:Orotic Acid; D013230:Stearoyl-CoA Desaturase