title: PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling.
abstract: The peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear receptors that regulate cellular homoeostasis and metabolism. PPARs control the expression of genes involved in fatty-acid and lipid metabolism. Despite evidence showing beneficial effects of their activation in the treatment of metabolic diseases, particularly dyslipidaemias and type 2 diabetes, PPAR agonists have also been associated with a variety of side effects and adverse pathological changes. Agonists have been developed that simultaneously activate the three PPAR receptors (PPARα, γ and δ) in the hope that the beneficial effects can be harnessed while avoiding some of the negative side effects. In this study, the hepatic effects of a discontinued PPAR-pan agonist (a triple agonist of PPAR-α, -γ, and -δ), was investigated after dietary treatment of male Sprague-Dawley (SD) rats. The agonist induced liver enlargement in conjunction with metabolomic and lipidomic remodelling. Increased concentrations of several metabolites related to processes of oxidation, such as oxo-methionine, methyl-cytosine and adenosyl-methionine indicated increased stress and immune status. These changes are reflected in lipidomic changes, and increased energy demands as determined by free fatty acid (decreased 18:3 n-3, 20:5 n-3 and increased ratios of n-6/n-3 fatty acids) triacylglycerol, phospholipid (decreased and increased bulk changes respectively) and eicosanoid content (increases in PGB2 and 15-deoxy PGJ2). We conclude that the investigated PPAR agonist, GW625019, induces liver enlargement, accompanied by lipidomic remodelling, oxidative stress and increases in several pro-inflammatory eicosanoids. This suggests that such pathways should be monitored in the drug development process and also outline how PPAR agonists induce liver proliferation.
authors.affiliation: Medical Research Council, Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK; The Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; The Cambridge Systems Biology Centre (CSBC), University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Ament
authors.affiliation: Medical Research Council, Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK; The Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; The Cambridge Systems Biology Centre (CSBC), University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: West
authors.affiliation: Medical Research Council, Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK; The Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; The Cambridge Systems Biology Centre (CSBC), University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stanley
authors.affiliation: Medical Research Council, Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK; The Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; The Cambridge Systems Biology Centre (CSBC), University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Ashmore
authors.affiliation: Medical Research Council, Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK; The Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; The Cambridge Systems Biology Centre (CSBC), University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Roberts
authors.affiliation: Jayne Wright Ltd., Underhill House, Ledbury, Herefordshire HR8 2QR, UK.
authors.forename: Jayne
authors.initials: J
authors.lastname: Wright
authors.affiliation: GlaxoSmithKline, Investigative Preclinical Toxicology, Park Road, Ware SG12 0DP, UK.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Nicholls
authors.affiliation: Medical Research Council, Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK; The Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; The Cambridge Systems Biology Centre (CSBC), University of Cambridge, Cambridge CB2 1QR, UK. Electronic address: jules.griffin@mrc-hnr.cam.ac.uk.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics*; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics*; D048068:PPAR-beta / Q000819:agonists / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005230:Fatty Acids, Nonesterified; D008055:Lipids; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta
keywords: Eicosanoids; Lipidomics; Metabolomics; Peroxisome proliferator-activated receptors; β-Oxidation