Project description: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 week treatment withfenofibrate and fish oil in mice. Plasma triglycerides were significantly decreased byfenofibrate (-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 PPARα, 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 towards 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. Expression profiling of liver from mice fed control diet, fish oil or fenofibrate for 2 weeks.
Project description: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 week treatment withfenofibrate and fish oil in mice. Plasma triglycerides were significantly decreased byfenofibrate (-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 PPARα, 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 towards 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.
Project description:The molecular effects of the non-selective dietary PPARalpha agonists n-3 LCPUFAs were compared side-by-side with those of the selective synthetic PPARalpha agonist fenofibrate on whole-genome gene expression in peripheral blood mononuclear cells (PBMCs), white adipose tissue (WAT), and muscle in overweight and obese subjects. Eleven overweight and obese subjects participated in a randomized, double-blind, placebo-controlled intervention trial and received in random order 3.7 g/d n-3 fatty acids (providing 1.7 g/d EPA and 1.2 g/d DHA), 200 mg fenofibrate or placebo treatment for 6 weeks separated by a wash-out period of at least 2-weeks. Fenofibrate changed 5 of the analysed 64 PPARalpha target genes in PBMC, 4 in muscle, and 2 in WAT, whereas fish oil changed 2 genes in WAT only. Both treatments changed 17 out of 25 similar pathways in PBMCs, related to xenobiotic metabolism, biosynthesis of steroids, lipid metabolism, transcription, proteasome function, Th1 immunity, propanoate metabolism and nucleotide metabolism. The majority (18 out of 25) of downregulated pathways in WAT were similarly changed in PBMCs after fish oil and related to lipid metabolism and amino acid metabolism. Fenofibrate and fish oil hardly affected pathways in muscle. In PBMCs, fenofibrate and fish oil only regulated 9 similar genes in metabolic syndrome-related pathways, which were IL25, TICAM1, PRDX2, PTGS1, AGK, FDPS, LDLR, TNNI3, LMAN1 and PTGS1. Overall, 6-weeks treatment with n-3 LCPUFAs and fenofibrate hardly affected PPARalpha target genes in overweight and obese subjects. Pathway analyses suggested that gene expression profiles in PBMCs can provide information about regulated metabolic processes by fish oil and fenofibrate in WAT, but not muscle. Expression of the individual genes, however, hardly overlapped between the tissues.
Project description:The molecular effects of the non-selective dietary PPARalpha agonists n-3 LCPUFAs were compared side-by-side with those of the selective synthetic PPARalpha agonist fenofibrate on whole-genome gene expression in peripheral blood mononuclear cells (PBMCs), white adipose tissue (WAT), and muscle in overweight and obese subjects. Eleven overweight and obese subjects participated in a randomized, double-blind, placebo-controlled intervention trial and received in random order 3.7 g/d n-3 fatty acids (providing 1.7 g/d EPA and 1.2 g/d DHA), 200 mg fenofibrate or placebo treatment for 6 weeks separated by a wash-out period of at least 2-weeks. Fenofibrate changed 5 of the analysed 64 PPARalpha target genes in PBMC, 4 in muscle, and 2 in WAT, whereas fish oil changed 2 genes in WAT only. Both treatments changed 17 out of 25 similar pathways in PBMCs, related to xenobiotic metabolism, biosynthesis of steroids, lipid metabolism, transcription, proteasome function, Th1 immunity, propanoate metabolism and nucleotide metabolism. The majority (18 out of 25) of downregulated pathways in WAT were similarly changed in PBMCs after fish oil and related to lipid metabolism and amino acid metabolism. Fenofibrate and fish oil hardly affected pathways in muscle. In PBMCs, fenofibrate and fish oil only regulated 9 similar genes in metabolic syndrome-related pathways, which were IL25, TICAM1, PRDX2, PTGS1, AGK, FDPS, LDLR, TNNI3, LMAN1 and PTGS1. Overall, 6-weeks treatment with n-3 LCPUFAs and fenofibrate hardly affected PPARalpha target genes in overweight and obese subjects. Pathway analyses suggested that gene expression profiles in PBMCs can provide information about regulated metabolic processes by fish oil and fenofibrate in WAT, but not muscle. Expression of the individual genes, however, hardly overlapped between the tissues.
Project description:The molecular effects of the non-selective dietary PPARalpha agonists n-3 LCPUFAs were compared side-by-side with those of the selective synthetic PPARalpha agonist fenofibrate on whole-genome gene expression in peripheral blood mononuclear cells (PBMCs), white adipose tissue (WAT), and muscle in overweight and obese subjects. Eleven overweight and obese subjects participated in a randomized, double-blind, placebo-controlled intervention trial and received in random order 3.7 g/d n-3 fatty acids (providing 1.7 g/d EPA and 1.2 g/d DHA), 200 mg fenofibrate or placebo treatment for 6 weeks separated by a wash-out period of at least 2-weeks. Fenofibrate changed 5 of the analysed 64 PPARalpha target genes in PBMC, 4 in muscle, and 2 in WAT, whereas fish oil changed 2 genes in WAT only. Both treatments changed 17 out of 25 similar pathways in PBMCs, related to xenobiotic metabolism, biosynthesis of steroids, lipid metabolism, transcription, proteasome function, Th1 immunity, propanoate metabolism and nucleotide metabolism. The majority (18 out of 25) of downregulated pathways in WAT were similarly changed in PBMCs after fish oil and related to lipid metabolism and amino acid metabolism. Fenofibrate and fish oil hardly affected pathways in muscle. In PBMCs, fenofibrate and fish oil only regulated 9 similar genes in metabolic syndrome-related pathways, which were IL25, TICAM1, PRDX2, PTGS1, AGK, FDPS, LDLR, TNNI3, LMAN1 and PTGS1. Overall, 6-weeks treatment with n-3 LCPUFAs and fenofibrate hardly affected PPARalpha target genes in overweight and obese subjects. Pathway analyses suggested that gene expression profiles in PBMCs can provide information about regulated metabolic processes by fish oil and fenofibrate in WAT, but not muscle. Expression of the individual genes, however, hardly overlapped between the tissues.
Project description:To investigate the differences in microRNA expression profiles between fibrotic and normal livers, we performed microRNA microarrays for total RNA extracts isolated from mouse livers treated with carbontetrachloride (CCl4) or corn-oil for 10 weeks (n=3/group). MicroRNAs were considered to have significant differences in expression level when the expression difference showed more than two-fold change between the experimental and control groups at p<0.05. We found that 12 miRNAs were differentially expressed in CCl4-induced fibrotic liver. To induce chronic liver fibrosis, seven-week-old mice received 0.6 ml/kg body weight of carbon-tetrachloride (CCl4) dissolved in corn-oil by intraperitoneal (i.p.) injection, twice a week for 10 weeks (n=3). As a control, same number of mice was injected with equal volume of corn-oil for 10 weeks.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.