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PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling.

Free Radic Biol Med. 2016 Jun;95:357-68. Epub 2015 Nov 30
Zsuzsanna Ament 1 , James A West 1 , Elizabeth Stanley 1 , Tom Ashmore 1 , Lee D Roberts 1 , Jayne Wright 2 , Andrew W Nicholls 3 , Julian L Griffin 4
Zsuzsanna Ament 1 , James A West 1 , Elizabeth Stanley 1 , Tom Ashmore 1 , Lee D Roberts 1 , Jayne Wright 2 , Andrew W Nicholls 3 , Julian L Griffin 4
+ et al

[No authors listed]

Author information
  • 1 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.
  • 2 Jayne Wright Ltd., Underhill House, Ledbury, Herefordshire HR8 2QR, UK.
  • 3 GlaxoSmithKline, Investigative Preclinical Toxicology, Park Road, Ware SG12 0DP, UK.
  • 4 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.

摘要


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.

KEYWORDS: Eicosanoids, Lipidomics, Metabolomics, Peroxisome proliferator-activated receptors, β-Oxidation