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Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin.
Goswami S, Yee SW, Stocker S, Mosley JD, Kubo M, Castro R, Mefford JA, Wen C, Liang X, Witte J, Brett C, Maeda S, Simpson MD, Hedderson MM, Davis RL, Roden DM, Giacomini KM, Savic RM
(2014) Clin Pharmacol Ther 96: 370-9
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study, Glycated Hemoglobin A, Hepatocyte Nuclear Factor 4, Homozygote, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Models, Biological, Multivariate Analysis, PPAR alpha, Pharmacogenetics, Phenotype, Polymorphism, Single Nucleotide, Retrospective Studies, Sp1 Transcription Factor, Transcription Factors, Treatment Outcome, United States, Young Adult
Show Abstract · Added June 26, 2014
One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.
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27 MeSH Terms
β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors.
Roberts LD, Boström P, O'Sullivan JF, Schinzel RT, Lewis GD, Dejam A, Lee YK, Palma MJ, Calhoun S, Georgiadi A, Chen MH, Ramachandran VS, Larson MG, Bouchard C, Rankinen T, Souza AL, Clish CB, Wang TJ, Estall JL, Soukas AA, Cowan CA, Spiegelman BM, Gerszten RE
(2014) Cell Metab 19: 96-108
MeSH Terms: Adipocytes, Brown, Adipocytes, White, Adipose Tissue, Brown, Adipose Tissue, White, Aminoisobutyric Acids, Animals, Cardiovascular Diseases, Cell Differentiation, Exercise, Gene Expression Regulation, Glucose Tolerance Test, Humans, Induced Pluripotent Stem Cells, Liver, Metabolic Diseases, Mice, Organ Specificity, Oxidation-Reduction, PPAR alpha, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phenotype, Physical Conditioning, Animal, Risk Factors, Transcription Factors, Transcription, Genetic, Weight Gain
Show Abstract · Added February 28, 2014
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
Copyright © 2014 Elsevier Inc. All rights reserved.
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26 MeSH Terms
PPARα activation can help prevent and treat non-small cell lung cancer.
Skrypnyk N, Chen X, Hu W, Su Y, Mont S, Yang S, Gangadhariah M, Wei S, Falck JR, Jat JL, Zent R, Capdevila JH, Pozzi A
(2014) Cancer Res 74: 621-31
MeSH Terms: Animals, Arachidonic Acids, Bezafibrate, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, Disease Models, Animal, Endothelial Cells, Female, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Male, Mice, Neoplasm Metastasis, Neoplasm Transplantation, Neovascularization, Pathologic, PPAR alpha, Pyrimidines
Show Abstract · Added February 25, 2014
Non-small cell lung cancer (NSCLC) not amenable to surgical resection has a high mortality rate, due to the ineffectiveness and toxicity of chemotherapy. Thus, there remains an urgent need of efficacious drugs that can combat this disease. In this study, we show that targeting the formation of proangiogenic epoxyeicosatrienoic acids (EET) by the cytochrome P450 arachidonic acid epoxygenases (Cyp2c) represents a new and safe mechanism to treat NSCLC growth and progression. In the transgenic murine K-Ras model and human orthotopic models of NSCLC, we found that Cyp2c44 could be downregulated by activating the transcription factor PPARα with the ligands bezafibrate and Wyeth-14,643. Notably, both treatments reduced primary and metastatic NSCLC growth, tumor angiogenesis, endothelial Cyp2c44 expression, and circulating EET levels. These beneficial effects were independent of the time of administration, whether before or after the onset of primary NSCLC, and they persisted after drug withdrawal, suggesting the benefits were durable. Our findings suggest that strategies to downregulate Cyp2c expression and/or its enzymatic activity may provide a safer and effective strategy to treat NSCLC. Moreover, as bezafibrate is a well-tolerated clinically approved drug used for managing lipidemia, our findings provide an immediate cue for clinical studies to evaluate the utility of PPARα ligands as safe agents for the treatment of lung cancer in humans.
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21 MeSH Terms
Rare PPARA variants and extreme response to fenofibrate in the Genetics of Lipid-Lowering Drugs and Diet Network Study.
Irvin MR, Zhang Q, Kabagambe EK, Perry RT, Straka RJ, Tiwari HK, Borecki IB, Shimmin LC, Stuart C, Zhong Y, Hixson JE, Arnett DK
(2012) Pharmacogenet Genomics 22: 367-72
MeSH Terms: Adult, Biomarkers, Pharmacological, Cholesterol, HDL, Cholesterol, LDL, Clinical Trials as Topic, Female, Fenofibrate, Gene Frequency, Genetic Association Studies, Haplotypes, Humans, Hypolipidemic Agents, Linkage Disequilibrium, Male, Middle Aged, PPAR alpha, Triglycerides
Show Abstract · Added March 7, 2014
OBJECTIVE - Fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) agonist, reduces triglyceride (TG) concentrations by 25-60%. Given significant interindividual variations in the TG response, we investigated the association of PPARA rare variants with treatment response in the Genetics of Lipid-Lowering Drugs and Diet Network study.
METHODS - We calculated the change in the TG concentration (ΔTG) among 861 GOLDN participants treated with fenofibrate (160 mg/day) for 3 weeks. From the distribution of ΔTG adjusted for age and sex, the 150 highest and 150 lowest fenofibrate responders were selected from the tails of the distribution for PPARA resequencing. The resequencing strategy was based on VariantSEQr technology for the amplification of exons and regulatory regions.
RESULTS - We identified 73 variants with an average minor allele frequency of 4.8% (range: 0.2-16%). We tested the association of rare variants located in a coding or a regulatory region (minor allele frequency<1%, 13 variants) with treatment response group by an indicator variable (presence/absence of ≥1 rare variant) using general linear mixed models to allow for adjustment for family relationship. After adjusting for baseline, fasting TG concentration carrying at least one rare variant was associated with a low fenofibrate response (odds ratio=6.46; 95% confidence interval: 1.4-30.8). Carrier status was also associated with a relative change in the total cholesterol concentration (P=0.02), but not high-density lipoprotein or low-density lipoprotein concentration.
CONCLUSION - Rare, potentially functional variants in PPARA may play a role in the TG response to fenofibrate, but future experimental studies will be necessary to replicate the findings and confirm functional effects.
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17 MeSH Terms
Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARalpha and FGF21 transcripts in vivo.
Berglund ED, Kang L, Lee-Young RS, Hasenour CM, Lustig DG, Lynes SE, Donahue EP, Swift LL, Charron MJ, Wasserman DH
(2010) Am J Physiol Endocrinol Metab 299: E607-14
MeSH Terms: Adenylate Kinase, Animals, Area Under Curve, Blood Glucose, Catecholamines, Fat Emulsions, Intravenous, Fatty Acids, Nonesterified, Female, Fibroblast Growth Factors, Glucagon, Glucose Clamp Technique, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, PPAR alpha, Physical Conditioning, Animal, RNA, Messenger, Receptors, Glucagon, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction
Show Abstract · Added December 10, 2013
Hepatic glucagon action increases in response to accelerated metabolic demands and is associated with increased whole body substrate availability, including circulating lipids. The hypothesis that increases in hepatic glucagon action stimulate AMP-activated protein kinase (AMPK) signaling and peroxisome proliferator-activated receptor-α (PPARα) and fibroblast growth factor 21 (FGF21) expression in a manner modulated by fatty acids was tested in vivo. Wild-type (gcgr(+/+)) and glucagon receptor-null (gcgr(-/-)) littermate mice were studied using an 18-h fast, exercise, and hyperglucagonemic-euglycemic clamps plus or minus increased circulating lipids. Fasting and exercise in gcgr(+/+), but not gcgr(-/-) mice, increased hepatic phosphorylated AMPKα at threonine 172 (p-AMPK(Thr(172))) and PPARα and FGF21 mRNA. Clamp results in gcgr(+/+) mice demonstrate that hyperlipidemia does not independently impact or modify glucagon-stimulated increases in hepatic AMP/ATP, p-AMPK(Thr(172)), or PPARα and FGF21 mRNA. It blunted glucagon-stimulated acetyl-CoA carboxylase phosphorylation, a downstream target of AMPK, and accentuated PPARα and FGF21 expression. All effects were absent in gcgr(-/-) mice. These findings demonstrate that glucagon exerts a critical regulatory role in liver to stimulate pathways linked to lipid metabolism in vivo and shows for the first time that effects of glucagon on PPARα and FGF21 expression are amplified by a physiological increase in circulating lipids.
1 Communities
2 Members
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23 MeSH Terms
Co-expression module analysis reveals biological processes, genomic gain, and regulatory mechanisms associated with breast cancer progression.
Shi Z, Derow CK, Zhang B
(2010) BMC Syst Biol 4: 74
MeSH Terms: Algorithms, Breast Neoplasms, Cell Adhesion, Cluster Analysis, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Models, Biological, Oligonucleotide Array Sequence Analysis, PPAR alpha, Risk Factors, Signal Transduction, Transcription Factors
Show Abstract · Added March 23, 2014
BACKGROUND - Gene expression signatures are typically identified by correlating gene expression patterns to a disease phenotype of interest. However, individual gene-based signatures usually suffer from low reproducibility and interpretability.
RESULTS - We have developed a novel algorithm Iterative Clique Enumeration (ICE) for identifying relatively independent maximal cliques as co-expression modules and a module-based approach to the analysis of gene expression data. Applying this approach on a public breast cancer dataset identified 19 modules whose expression levels were significantly correlated with tumor grade. The correlations were reproducible for 17 modules in an independent breast cancer dataset, and the reproducibility was considerably higher than that based on individual genes or modules identified by other algorithms. Sixteen out of the 17 modules showed significant enrichment in certain Gene Ontology (GO) categories. Specifically, modules related to cell proliferation and immune response were up-regulated in high-grade tumors while those related to cell adhesion was down-regulated. Further analyses showed that transcription factors NYFB, E2F1/E2F3, NRF1, and ELK1 were responsible for the up-regulation of the cell proliferation modules. IRF family and ETS family proteins were responsible for the up-regulation of the immune response modules. Moreover, inhibition of the PPARA signaling pathway may also play an important role in tumor progression. The module without GO enrichment was found to be associated with a potential genomic gain in 8q21-23 in high-grade tumors. The 17-module signature of breast tumor progression clustered patients into subgroups with significantly different relapse-free survival times. Namely, patients with lower cell proliferation and higher cell adhesion levels had significantly lower risk of recurrence, both for all patients (p = 0.004) and for those with grade 2 tumors (p = 0.017).
CONCLUSIONS - The ICE algorithm is effective in identifying relatively independent co-expression modules from gene co-expression networks and the module-based approach illustrated in this study provides a robust, interpretable, and mechanistic characterization of transcriptional changes.
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15 MeSH Terms
The anti-tumorigenic properties of peroxisomal proliferator-activated receptor alpha are arachidonic acid epoxygenase-mediated.
Pozzi A, Popescu V, Yang S, Mei S, Shi M, Puolitaival SM, Caprioli RM, Capdevila JH
(2010) J Biol Chem 285: 12840-50
MeSH Terms: Animals, Cell Proliferation, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, Drug Screening Assays, Antitumor, Endothelium, Vascular, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Knockout, Neoplasm Proteins, Neoplasm Transplantation, Neoplasms, Experimental, Neovascularization, Pathologic, PPAR alpha, Transplantation, Heterologous
Show Abstract · Added February 24, 2014
Prevalence and mortality make cancer a health challenge in need of effective and better tolerated therapeutic approaches, with tumor angiogenesis identified as a promising target for drug development. The epoxygenase products, the epoxyeicosatrienoic acids, are pro-angiogenic, and down-regulation of their biosynthesis by peroxisomal proliferator-activated receptor alpha (PPARalpha) ligands reduces tumor angiogenesis and growth. Endothelial cells lacking a Cyp2c44 epoxygenase, a PPARalpha target, show reduced proliferative and tubulogenic activities that are reversed by the enzyme's metabolites. In a mouse xenograft model of tumorigenesis, disruption of the host Cyp2c44 gene causes marked reductions in tumor volume, mass, and vascularization. The relevance of these studies to human cancer is indicated by the demonstration that: (a) activation of human PPARalpha down-regulates endothelial cell CYP2C9 epoxygenase expression and blunts proliferation and tubulogenesis, (b) in a PPARalpha-humanized mouse model, activation of the receptor inhibits tumor angiogenesis and growth, and (c) the CYP2C9 epoxygenase is expressed in the vasculature of human tumors. The identification of anti-angiogenic/anti-tumorigenic properties of PPARalpha points to a role for the receptor and its epoxygenase regulatory target in the pathophysiology of cancer, and for its ligands as candidates for the development of a new generation of safer and better tolerated anti-cancer drugs.
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17 MeSH Terms
Macrophage expression of peroxisome proliferator-activated receptor-alpha reduces atherosclerosis in low-density lipoprotein receptor-deficient mice.
Babaev VR, Ishiguro H, Ding L, Yancey PG, Dove DE, Kovacs WJ, Semenkovich CF, Fazio S, Linton MF
(2007) Circulation 116: 1404-12
MeSH Terms: Animals, Aortic Diseases, Atherosclerosis, Biological Transport, Bone Marrow Transplantation, Butyrates, Cells, Cultured, Female, Gene Expression Regulation, Inflammation, Lipid Metabolism, Lipoproteins, LDL, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, PPAR alpha, Phenylurea Compounds, Pyrimidines, Radiation Chimera, Receptors, LDL
Show Abstract · Added December 10, 2013
BACKGROUND - The peroxisome proliferator-activated receptor-alpha (PPARalpha) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPARalpha ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARalpha expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes.
METHODS AND RESULTS - To examine the contribution of PPARalpha expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein receptor-deficient (LDLR(-/-)) mice were reconstituted with bone marrow from PPARalpha(-/-) or PPARalpha(+/+) mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPARalpha(-/-) --> LDLR(-/-) mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPARalpha(-/-) --> LDLR(-/-) mice also had larger (44%) atherosclerotic lesions in the proximal aorta than male PPARalpha(+/+) --> LDLR(-/-) mice. Peritoneal macrophages from PPARalpha(-/-) mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPARalpha(-/-) macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-kappaB-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-kappaB gene expression levels in vivo in atherosclerotic lesions of PPARalpha(-/-) --> LDLR(-/-) mice compared with the lesions of control PPARalpha(+/+) --> LDLR(-/-) mice.
CONCLUSIONS - These data demonstrate that PPARalpha expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.
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22 MeSH Terms
Epidermal lipoxygenase products of the hepoxilin pathway selectively activate the nuclear receptor PPARalpha.
Yu Z, Schneider C, Boeglin WE, Brash AR
(2007) Lipids 42: 491-7
MeSH Terms: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid, 8,11,14-Eicosatrienoic Acid, Arachidonate Lipoxygenases, Cell Differentiation, Cell Line, Epidermal Cells, Epidermis, Genes, Reporter, Humans, Hydroxyeicosatetraenoic Acids, Lipoxygenase, Luciferases, PPAR alpha, PPAR delta, PPAR gamma, Receptors, Cytoplasmic and Nuclear, Signal Transduction
Show Abstract · Added December 10, 2013
Arachidonic acid can be transformed into a specific epoxyalcohol product via the sequential action of two epidermal lipoxygenases, 12R-LOX and eLOX3. Functional impairment of either lipoxygenase gene (ALOX12B or ALOXE3) results in ichthyosis, suggesting a role for the common epoxyalcohol product or its metabolites in the differentiation of normal human skin. Here we tested the ability of products derived from the epidermal LOX pathway to activate the peroxisome proliferator-activated receptors PPARalpha, gamma, and delta, which have been implicated in epidermal differentiation. Using a dual luciferase reporter assay in PC3 cells, the 12R-LOX/eLOX3-derived epoxyalcohol, 8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid, activated PPARalpha with similar in potency to the known natural ligand, 8S-hydroxyeicosatetraenoic acid (8S-HETE) (both at 10 microM concentration). In contrast, the PPARgamma and PPARdelta receptor isoforms were not activated by the epoxyalcohol. Activation of PPARalpha was also observed using the trihydroxy hydrolysis products (trioxilins) of the unstable epoxyalcohol. Of the four trioxilins isolated and characterized, the highest activation was observed with the isomer that is also formed by enzymatic hydrolysis of the epoxyalcohol. Formation of a ligand for the nuclear receptor PPARalpha may be one possibility by which 12R-LOX and eLOX3 contribute to epidermal differentiation.
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17 MeSH Terms
Peroxisomal proliferator-activated receptor-alpha-dependent inhibition of endothelial cell proliferation and tumorigenesis.
Pozzi A, Ibanez MR, Gatica AE, Yang S, Wei S, Mei S, Falck JR, Capdevila JH
(2007) J Biol Chem 282: 17685-95
MeSH Terms: Animals, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Cytochrome P-450 Enzyme System, Eicosanoids, Endothelial Cells, Liver, Lung, Mice, Mice, Inbred BALB C, Mice, Knockout, Neoplasm Transplantation, Neovascularization, Pathologic, PPAR alpha, Pyrimidines
Show Abstract · Added February 24, 2014
The peroxisomal proliferator-activated nuclear receptor-alpha (PPARalpha), the target for most hypolipidemic drugs in current clinical use, regulates the transcription of genes involved in lipid metabolism and transport, and energy homeostasis. More recently, PPARalpha and its ligands have been implicated in inflammatory responses and the regulation of cell proliferation. PPARalpha also regulates the expression of Cyp4a fatty acid omega-hydroxylases and Cyp2c arachidonic acid epoxygenase genes. To study the role of the PPARalpha receptor and of its Cyp2c epoxygenase gene target in tumorigenesis, we treated mice injected with tumor cells with Wy-14,643, a PPARalpha-selective ligand. Compared with untreated controls, Wy-14643-treated animals showed marked reductions in tumor growth and vascularization, which were accompanied by decreases in the plasma levels of pro-angiogenic epoxygenase metabolites (EETs), hepatic EET biosynthesis, and Cyp2c epoxygenase expression. All these Wy-14643-induced responses were absent in PPARalpha(-/-) mice and are thus PPARalpha-mediated. Primary cultures of mouse lung endothelial cells treated with Wy-14643 showed reductions in cell proliferation and in the formation of capillary-like structures. These effects were absent in cells obtained from PPRAalpha(-/-) mice and reversed by the addition of EETs. These results identify important anti-angiogenic and anti-tumorigenic roles for PPARalpha, characterize the contribution of its Cyp2c epoxygenases gene target to these responses, and suggest potential anti-cancer roles for this nuclear receptor and its ligands.
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16 MeSH Terms