Protein expression changes in the Sprague Dawley rat liver proteome following administration of peroxisome proliferator activated receptor alpha and gamma ligands.
Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily and are intimately involved in lipid metabolism and energy homeostasis. Activation of these receptors in rodents can lead to hepatomegaly and ultimately hepatic carcinogenesis although the mechanisms by which these processes occur are poorly understood. To further our understanding of these processes and to discriminate between different PPAR mediated signalling pathways, a proteomic approach has been undertaken to identify changes in protein expression patterns in Sprague Dawley rat liver following dosing with a PPARalpha agonist (Wyeth 14643), a PPARgamma agonist (Troglitazone) and a compound with mixed PPARalpha/gamma agonist activity (SB-219994). Using one-and-two-dimensional electrophoresis of tissue lysates a diverse range of protein abundance changes was observed in these tissues. Whilst a number of these proteins have PPAR response elements (PPREs) in their respective promoters, another group was detected whose expression has been documented to be sensitive to peroxisome proliferator administration. Most notably within these groups, proteins involved in lipid catabolism displayed increased expression following drug administration. A further subset of proteins, with less obvious biological implications, also showed altered expression patterns. Where available, sequences upstream of the coding regions of genes not previously known to have PPREs were searched with positional consensus matrices for the presence of PPREs in an attempt to validate these changes. Using such an approach putative PPARgamma and PPARdelta response elements were discovered upstream of the tubulin beta coding region. There was limited overlap in observed protein abundance changes between the three groups, and where this was the case (cytosolic epoxide hydrolase, peroxisomal bifunctional enzyme, hydroxymethyl glutaryl CoA, synthase, long chain acyl-CoA thioesterase), expression of these proteins had previously been shown to be under the control of PPAR activity.
White
Ian R
IR
Departments of Genomic and Proteomic Sciences, GlaxoSmithKline Pharmaceuticals, Medicines Research Centre, Stevenage, Herts, UK. ian_r_white@gsk.com
Man
Wai J
WJ
Bryant
Duncan
D
Bugelski
Peter
P
Camilleri
Patrick
P
Cutler
Paul
P
Hayes
William
W
Holbrook
Joanna D
JD
Kramer
Kerstin
K
Lord
Peter G
PG
Wood
John
J
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D005786:Gene Expression Regulation / Q000187:drug effects*; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020543:Proteome / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D000077288:Troglitazone
D001583:Benzoxazoles; D002839:Chromans; D008024:Ligands; D020025:Peroxisome Proliferators; D020543:Proteome; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; C480767:SB219994; D045162:Thiazolidinediones; D014157:Transcription Factors; C006253:pirinixic acid; D000077288:Troglitazone