title: Comparative transcriptomic and metabolomic analysis of fenofibrate and fish oil treatments in mice.
abstract: Elevated circulating triglycerides, which are considered a risk factor for cardiovascular disease, can be targeted by treatment with fenofibrate or fish oil. To gain insight into underlying mechanisms, we carried out a comparative transcriptomics and metabolomics analysis of the effect of 2 wk treatment with fenofibrate and fish oil in mice. Plasma triglycerides were significantly decreased by fenofibrate (-49.1%) and fish oil (-21.8%), whereas plasma cholesterol was increased by fenofibrate (+29.9%) and decreased by fish oil (-32.8%). Levels of various phospholipid species were specifically decreased by fish oil, while levels of Krebs cycle intermediates were increased specifically by fenofibrate. Plasma levels of many amino acids were altered by fenofibrate and to a lesser extent by fish oil. Both fenofibrate and fish oil upregulated genes involved in fatty acid metabolism and downregulated genes involved in blood coagulation and fibrinolysis. Significant overlap in gene regulation by fenofibrate and fish oil was observed, reflecting their property as high or low affinity agonist for peroxisome proliferator-activated receptor-α, respectively. Fenofibrate specifically downregulated genes involved in complement cascade and inflammatory response. Fish oil specifically downregulated genes involved in cholesterol and fatty acid biosynthesis and upregulated genes involved in amino acid and arachidonic acid metabolism. Taken together, the data indicate that despite being similarly potent toward modulating plasma free fatty acids, cholesterol, and triglyceride levels, fish oil causes modest changes in gene expression likely via activation of multiple mechanistic pathways, whereas fenofibrate causes pronounced gene expression changes via a single pathway, reflecting the key difference between nutritional and pharmacological intervention.
authors.affiliation: Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Yingchang
authors.initials: Y
authors.lastname: Lu
authors.forename: Mark V
authors.initials: MV
authors.lastname: Boekschoten
authors.forename: Suzan
authors.initials: S
authors.lastname: Wopereis
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
mesh_terms: D000596:Amino Acids / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D005227:Fatty Acids / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects; D005395:Fish Oils / Q000494:pharmacology*; D020869:Gene Expression Profiling; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010743:Phospholipids / Q000097:blood; D018709:Statistics, Nonparametric; D059467:Transcriptome / Q000187:drug effects*; D014280:Triglycerides / Q000097:blood
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D005395:Fish Oils; D047492:Peroxisome Proliferator-Activated Receptors; D010743:Phospholipids; D014280:Triglycerides; D002784:Cholesterol; D011345:Fenofibrate