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[PMID]: 29524400
[Au] Autor:Ren G; Rimando AM; Mathews ST
[Ad] Address:Department of Nutrition and Dietetics, Boshell Diabetes and Metabolic Diseases Research Program, Auburn University, AL 36849, USA.
[Ti] Title:AMPK activation by pterostilbene contributes to suppression of hepatic gluconeogenic gene expression and glucose production in H4IIE cells.
[So] Source:Biochem Biophys Res Commun;, 2018 Mar 07.
[Is] ISSN:1090-2104
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Pterostilbene, a bioactive component of blueberries and grapes, shows structural similarity to resveratrol, and exhibits antioxidant, anti-inflammatory, anti-cancer, hypoglycemic, and cholesterol lowering effects. Recent evidence indicates that pterostilbene is an agonist of the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-α). Since PPAR-α agonists induce peroxisomal proliferation and fatty acid oxidation, we examined gene expression of acyl CoA oxidase (ACO) and carnitine palmitoyl transferase-1 (CPT-1). Pterostilbene treatment, at concentrations that demonstrated over 75% cell viability (20 µM, 50 µM), significantly increased gene expression of ACO, CPT-1, and PPAR-α. Pterostilbene treatment (50 µM) also demonstrated potent activation of AMP-activated kinase (AMPK), compared to AICAR (0.5 mM) or metformin (2 mM), consistent with upregulation in fatty acid oxidation gene expression. Since AMPK activators mimic the actions of insulin by repressing hepatic gluconeogenesis, we examined pterostilbene's effects on hepatic gluconeogenic gene expression. Pterostilbene treatment significantly repressed dexamethasone-induced phosphoenol pyruvate carboxykinase (PEPCK) and glucose6-phosphatase (G6Pase) gene expression, and decreased glucose production in H4IIE cells. Taken together, our studies demonstrate that pterostilbene, a natural compound and PPAR-α agonist, modulate several AMPK-dependent metabolic functions. The results of the present study suggest that pterostilbene may have beneficial effects in the prevention and management of type 2 diabetes and related disorders. In this study, we found that pterostilbene activated AMP-activated kinase (AMPK) and increased the expression of fatty acid oxidation genes, including acyl CoA oxidase and carnitine palmitoyl transferase-1.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  2 / 11093 MEDLINE  
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[PMID]: 29175453
[Au] Autor:Zhang Y; Lickteig AJ; Csanaky IL; Klaassen CD
[Ad] Address:School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China. Electronic address: youcai.zhang@tju.edu.cn.
[Ti] Title:Activation of PPARα decreases bile acids in livers of female mice while maintaining bile flow and biliary bile acid excretion.
[So] Source:Toxicol Appl Pharmacol;338:112-123, 2018 01 01.
[Is] ISSN:1096-0333
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Fibrates are hypolipidemic drugs that act as activators of peroxisome proliferator-activated receptor α (PPARα). In both humans and rodents, females were reported to be less responsive to fibrates than males. Previous studies on fibrates and PPARα usually involved male mice, but little has been done in females. The present study aimed to provide the first comprehensive analysis of the effects of clofibrate (CLOF) and PPARα on bile acid (BA) homeostasis in female mice. Study in WT male mice showed that a 4-day CLOF treatment increased liver weight, bile flow, and biliary BA excretion, but decreased total BAs in both serum and liver. In contrast, WT female mice were less susceptible to these CLOF-mediated responses observed in males. In WT female mice, CLOF decreased total BAs in the liver, but had little effect on the mRNAs of hepatic BA-related genes. Next, a comparative analysis between WT and PPARα-null female mice showed that lack of PPARα in female mice decreased total BAs in serum, but had little effect on total BAs in liver or bile. However, lack of PPARα in female mice increased mRNAs of BA synthetic enzymes (Cyp7a1, Cyp8b1, Cyp27a1, and Cyp7b1) and transporters (Ntcp, Oatp1a1, Oatp1b2, and Mrp3). Furthermore, the increase of Cyp7a1 in PPARα-null female mice was associated with an increase in liver Fxr-Shp-Lrh-1 signaling. In conclusion, female mice are resistant to CLOF-mediated effects on BA metabolism observed in males, which could be attributed to PPARα-mediated suppression in females on genes involved in BA synthesis and transport.
[Mh] MeSH terms primary: Bile Acids and Salts/metabolism
Bile/metabolism
Liver/metabolism
PPAR alpha/physiology
[Mh] MeSH terms secundary: Animals
Cholesterol/metabolism
Cholesterol 7-alpha-Hydroxylase/genetics
Clofibrate/pharmacology
Female
Ileum/metabolism
Mice
Mice, Inbred C57BL
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Name of substance:0 (Bile Acids and Salts); 0 (PPAR alpha); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse); HPN91K7FU3 (Clofibrate)
[Em] Entry month:1801
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[Js] Journal subset:IM
[Da] Date of entry for processing:171128
[St] Status:MEDLINE

  3 / 11093 MEDLINE  
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[PMID]: 29476879
[Au] Autor:Ren T; Yang WS; Lin Y; Liu JF; Li Y; Yang LC; Zeng KY; Peng L; Liu YJ; Ye ZH; Luo XM; Ke YJ; Diao Y; Jin X
[Ad] Address:School of Biomedical Science, Institute of Molecular Medicine, Huaqiao University, Quanzhou 612021, China.
[Ti] Title:A novel PPARα/γ agonist, propane-2-sulfonic acid octadec-9-enyl-amide, ameliorates insulin resistance and gluconeogenesis in vivo and vitro.
[So] Source:Eur J Pharmacol;826:1-8, 2018 Feb 22.
[Is] ISSN:1879-0712
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ) agonists have emerged as important pharmacological agents for improving insulin action. Propane-2-sulfonic acid octadec-9-enyl-amide (N15) is a novel PPARα/γ dual agonist synthesized in our laboratory. The present study investigates the efficacy and safety of N15 on insulin resistance regulation in high fat diet (HFD)-and streptozotocin (STZ)-induced diabetic mice and in palmitic acid (PA)-induced HepG2 cells. Our results showed that N15 remarkably ameliorated insulin resistance and dyslipidemia in vivo, as well as rectified the glucose consumption and gluconeogenesis in vitro. Moreover, the glucose-lowering effect of N15 was associated with PPARγ mediated up-regulation of hepatic glucose consumption and down-regulation of gluconeogenesis. Meanwhile, N15 exerted advantageous effects on glucose and lipid metabolism without triggering weight gain and hepatotoxicity in mice. In conclusion, our data demonstrated that by alleviating glucose and lipid abnormalities, N15 could be used as a potential prophylactic and therapeutic agent against type 2 diabetes and related metabolic disorders.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher

  4 / 11093 MEDLINE  
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[PMID]: 29510153
[Au] Autor:Szczepanska AA; Lupicka M; Socha BM; Korzekwa AJ
[Ad] Address:Department of Biodiversity Protection, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Olsztyn, Tuwima St. 10, 10-747 Olsztyn, Poland.
[Ti] Title:The influence of arachidonic acid metabolites on PPAR and RXR expression in bovine uterine cells.
[So] Source:Gen Comp Endocrinol;, 2018 Mar 03.
[Is] ISSN:1095-6840
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the superfamily of nuclear receptors. Three isoforms have been described: alpha (PPARα), delta (PPARδ), and gamma (PPARγ). PPARs heterodimerize with retinoid X receptors (RXRs: RXRα, RXRß and RXRγ). PPAR activity can be modulated by several ligands, including arachidonic acid (AA) metabolites. The aims of the study were to determine the effect of AA metabolites (prostaglandin [PG]E , PGF , leukotriene [LT]B , and LTC ) on mRNA (real-time PCR) and protein expression (Western blotting) of PPARα, PPARδ, and PPARγ, and on mRNA expression of RXRα, RXRß, and RXRγ, in bovine epithelial, stromal, and myometrial primary uterine cells and in bovine stromal cells with silenced PPAR genes (N=10). All PPAR and RXR isoforms were expressed. Prostaglandins affected expression of PPARs only in stromal cells, whereas LTs modulated PPARγ mRNA expression in epithelial and myometrial primary cells. Blockade of signal transduction through PPARs prevented interactions between AA metabolites and PPARs and changed RXR expression comparing with primary stromal cells. In primary stromal uterine cells, mRNA expression of RXRs was higher than that of PPARs. In uterine stromal cells in which intracellular signaling through PPARs was blocked, RXRs seem to take over the role of PPARs and are pivotal for cell functions. This study revealed the reaction of PPARs and RXRs to agonists which naturally occur in the bovine uterus.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180306
[Lr] Last revision date:180306
[St] Status:Publisher

  5 / 11093 MEDLINE  
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[PMID]: 29367637
[Au] Autor:Zhang X; Ma ZG; Yuan YP; Xu SC; Wei WY; Song P; Kong CY; Deng W; Tang QZ
[Ad] Address:Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
[Ti] Title:Rosmarinic acid attenuates cardiac fibrosis following long-term pressure overload via AMPKα/Smad3 signaling.
[So] Source:Cell Death Dis;9(2):102, 2018 Jan 24.
[Is] ISSN:2041-4889
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Agonists of peroxisome proliferator-activated receptor gamma (PPAR-γ) can activate 5' AMP-activated protein kinase alpha (AMPKα) and exert cardioprotective effects. A previous study has demonstrated that rosmarinic acid (RA) can activate PPAR-γ, but its effect on cardiac remodeling remains largely unknown. Our study aimed to investigate the effect of RA on cardiac remodeling and to clarify the underlying mechanism. Mice were subjected to aortic banding to generate pressure overload induced cardiac remodeling and then were orally administered RA (100 mg/kg/day) for 7 weeks beginning 1 week after surgery. The morphological examination, echocardiography, and molecular markers were used to evaluate the effects of RA. To ascertain whether the beneficial effect of RA on cardiac fibrosis was mediated by AMPKα, AMPKα2 knockout mice were used. Neonatal rat cardiomyocytes and fibroblasts were separated and cultured to validate the protective effect of RA in vitro. RA-treated mice exhibited a similar hypertrophic response as mice without RA treatment, but had an attenuated fibrotic response and improved cardiac function after pressure overload. Activated AMPKα was essential for the anti-fibrotic effect of RA via inhibiting the phosphorylation and nuclear translocation of Smad3 in vivo and in vitro, and AMPKα deficiency abolished RA-mediated protective effects. Small interfering RNA against Ppar-γ (siPpar-γ) and GW9662, a specific antagonist of PPAR-γ, abolished RA-mediated AMPKα phosphorylation and alleviation of fibrotic response in vitro. RA attenuated cardiac fibrosis following long-term pressure overload via AMPKα/Smad3 signaling and PPAR-γ was required for the activation of AMPKα. RA might be a promising therapeutic agent against cardiac fibrosis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:In-Data-Review
[do] DOI:10.1038/s41419-017-0123-3

  6 / 11093 MEDLINE  
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[PMID]: 28453233
[Au] Autor:Huang YP; Chang NW
[Ad] Address:Department of Physiology, College of Medicine, China Medical University, Taichung, Taiwan.
[Ti] Title:Proteomic analysis of oral cancer reveals new potential therapeutic targets involved in the Warburg effect.
[So] Source:Clin Exp Pharmacol Physiol;44(8):880-887, 2017 Aug.
[Is] ISSN:1440-1681
[Cp] Country of publication:Australia
[La] Language:eng
[Ab] Abstract:Activation of peroxisome proliferator-activated receptor alpha (PPARα) has been reported to disrupt tumour metabolism and to promote anticancer activity through interfering with the Warburg effect. This study is to investigate whether Warburg effect-related proteins also could be identified in oral tumour lesions and to explore the functional significance of PPARα in metabolic shift. Five pairs of tongue tumour tissues and adjacent reference tissues obtained from 4-NQO/arecoline induced mouse model were analyzed by 2-d-gel-electrophoresis and LC-MS. Further, the hexokinase II level, pyruvate dehydrogenase (PDH) activity, and metabolites of glycolysis and TCA cycle were all examined in order to validate the effect of PPARα on metabolic shift. Changes in protein expression levels revealed that seven proteins, which were involved in glycolysis, the tricarboxylic acid cycle, and the respiratory chain, were down-regulated in tumour tissues. We found that activation of PPARα through fenofibrate could inhibit oral cancer cell growth and switch the way of energy production from the Warburg effect to oxidative phosphorylation. Fenofibrate induced a reduction of hexokinase II protein levels, increases in PDH activity and metabolites of the TCA cycle, and an impairment of ATP production. These findings suggested that activation of the PPARα to reprogram the metabolic pathway might impair the Warburg effect and trigger cancer cell death. The study provides a novel view of changes in protein expression profiles involved in the Warburg effect during oral tumourigenesis. Activation of the PPARα to impair the Warburg effect might offer a new strategy for oral cancer treatment.
[Mh] MeSH terms primary: Molecular Targeted Therapy
Mouth Neoplasms/drug therapy
Mouth Neoplasms/metabolism
Proteomics
[Mh] MeSH terms secundary: Animals
Citric Acid Cycle/drug effects
Glycolysis/drug effects
Male
Mice
Mice, Inbred C57BL
Mouth Neoplasms/pathology
Oxidative Phosphorylation/drug effects
PPAR alpha/metabolism
Signal Transduction/drug effects
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (PPAR alpha)
[Em] Entry month:1803
[Cu] Class update date: 180306
[Lr] Last revision date:180306
[Js] Journal subset:IM
[Da] Date of entry for processing:170429
[St] Status:MEDLINE
[do] DOI:10.1111/1440-1681.12774

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[PMID]: 29351550
[Au] Autor:Rachid TL; Silva-Veiga FM; Graus-Nunes F; Bringhenti I; Mandarim-de-Lacerda CA; Souza-Mello V
[Ad] Address:Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
[Ti] Title:Differential actions of PPAR-α and PPAR-ß/δ on beige adipocyte formation: A study in the subcutaneous white adipose tissue of obese male mice.
[So] Source:PLoS One;13(1):e0191365, 2018.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND AND AIMS: Obesity compromises adipocyte physiology. PPARs are essential to adipocyte plasticity, but its isolated role in the browning phenomenon is not clear. This study aimed to examine whether activation of PPAR-α or PPAR-ß/δ could induce beige cell depots in the subcutaneous white adipose tissue of diet-induced obese mice. MATERIAL AND METHODS: Sixty animals were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for ten weeks. Then each group was re-divided to begin the treatments that lasted 4 weeks, totalizing six groups: C, C-α (C plus PPAR-α agonist, 2.5 mg/kg BM), C-ß (C plus PPAR-ß/δ agonist, 1 mg/kg BM), HF, HF-α (HF plus PPAR-α agonist), HF-ß (HF plus PPAR-ß/δ agonist). RESULTS: HF animals presented with overweight, glucose intolerance and subcutaneous white adipocyte hypertrophy. Both treatments significantly attenuated these parameters. Browning, verified by UCP1 positive beige cells and enhanced body temperature, was just observed in PPAR-α treated groups. PPAR-α agonism also elicited an enhanced gene expression of the thermogenesis effector UCP1, the beige-selective gene TMEM26 and the PRDM16, an essential gene for brown-like phenotype maintenance in the beige adipocytes when compared to their counterparts. The enhanced CIDEA and the reduced UCP1 gene levels might justify the white phenotype predominance after the treatment with the PPAR-ß/δ agonist. CONCLUSIONS: This work provides evidence that the PPAR-ß/δ agonist ameliorated metabolic disorders through enhanced beta-oxidation and better tolerance to glucose, whereas the PPAR-α agonism was confirmed as a promising therapeutic target for treating metabolic diseases via beige cell induction and enhanced thermogenesis.
[Mh] MeSH terms primary: Adipocytes, Beige/drug effects
Obesity/drug therapy
PPAR alpha/agonists
PPAR delta/agonists
PPAR-beta/agonists
[Mh] MeSH terms secundary: Adipocytes, Beige/metabolism
Adipocytes, Beige/pathology
Adipose Tissue, White/drug effects
Adipose Tissue, White/metabolism
Adipose Tissue, White/pathology
Adiposity/drug effects
Animals
Blood Glucose/metabolism
Body Weight/drug effects
Cell Size/drug effects
Diet, High-Fat/adverse effects
Energy Intake/drug effects
Gene Expression/drug effects
Glucose Intolerance/drug therapy
Hyperinsulinism/drug therapy
Male
Mice
Mice, Inbred C57BL
Obesity/metabolism
Obesity/pathology
Thermogenesis/drug effects
Uncoupling Protein 1/metabolism
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Blood Glucose); 0 (PPAR alpha); 0 (PPAR delta); 0 (PPAR-beta); 0 (Ucp1 protein, mouse); 0 (Uncoupling Protein 1)
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[Js] Journal subset:IM
[Da] Date of entry for processing:180120
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191365

  8 / 11093 MEDLINE  
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[PMID]: 29502862
[Au] Autor:Nierenberg AA; Ghaznavi SA; Sande Mathias I; Ellard KK; Janos JA; Sylvia LG
[Ad] Address:Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address: anierenberg@mgh.harvard.edu.
[Ti] Title:Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha as a Novel Target for Bipolar Disorder and Other Neuropsychiatric Disorders.
[So] Source:Biol Psychiatry;, 2018 Jan 10.
[Is] ISSN:1873-2402
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a protein that regulates metabolism and inflammation by activating nuclear receptors, especially the family of peroxisome proliferator-activated receptors (PPARs). PGC-1 alpha and PPARs also regulate mitochondrial biogenesis, cellular energy production, thermogenesis, and lipid metabolism. Brain energy metabolism may also be regulated in part by the interaction between PGC-1 alpha and PPARs. Because neurodegenerative diseases (Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis) and bipolar disorder have been associated with dysregulated mitochondrial and brain energy metabolism, PGC-1 alpha may represent a potential drug target for these conditions. The purpose of this article is to review the physiology of PGC-1 alpha, PPARs, and the role of PPAR agonists to target PGC-1 alpha to treat neurodegenerative diseases and bipolar disorder. We also review clinical trials of repurposed antidiabetic thiazolidines and anti-triglyceride fibrates (PPAR agonists) for neurodegenerative diseases and bipolar disorder. PGC-1 alpha and PPARs are innovative potential targets for bipolar disorder and warrant future clinical trials.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[St] Status:Publisher

  9 / 11093 MEDLINE  
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[PMID]: 29502000
[Au] Autor:Yang D; Jiang H; Lu J; Lv Y; Baiyun R; Li S; Liu B; Lv Z; Zhang Z
[Ad] Address:College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
[Ti] Title:Dietary grape seed proanthocyanidin extract regulates metabolic disturbance in rat liver exposed to lead associated with PPARα signaling pathway.
[So] Source:Environ Pollut;237:377-387, 2018 Mar 01.
[Is] ISSN:1873-6424
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Lead, a pervasive environmental hazard worldwide, causes a wide range of physiological and biochemical destruction, including metabolic dysfunction. Grape seed proanthocyanidin extract (GSPE) is a natural production with potential metabolic regulation in liver. This study was performed to investigate the protective role of GSPE against lead-induced metabolic dysfunction in liver and elucidate the potential molecular mechanism of this event. Wistar rats received GSPE (200 mg/kg) daily with or without lead acetate (PbA, 0.5 g/L) exposure for 56 d. According to biochemical and histopathologic analysis, GSPE attenuated lead-induced metabolic dysfunction, oxidative stress, and liver dysfunction. Liver gene expression profiling was assessed by RNA sequencing and validated by qRT-PCR. Expression of some genes in peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway was significantly suppressed in PbA group and revived in PbA + GSPE group, which was manifested by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated by western blot analysis. This study supports that dietary GSPE ameliorates lead-induced fatty acids metabolic disturbance in rat liver associated with PPARα signaling pathway, and suggests that dietary GSPE may be a protector against lead-induced metabolic dysfunction and liver injury, providing a novel therapy to protect liver against lead exposure.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180304
[Lr] Last revision date:180304
[St] Status:Publisher

  10 / 11093 MEDLINE  
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[PMID]: 29500923
[Au] Autor:Ozurumba E; Mathew O; Ranganna K; Choi M; Oyekan A
[Ad] Address:Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
[Ti] Title:Regulation of hypoxia inducible factor/prolyl hydroxylase binding domain proteins 1 by PPARα and high salt diet.
[So] Source:J Basic Clin Physiol Pharmacol;29(2):165-173, 2018 Mar 28.
[Is] ISSN:2191-0286
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:BACKGROUND: Hypoxia inducible factor (HIF)/prolyl hydroxylase domain (PHD)-containing proteins are involved in renal adaptive response to high salt (HS). Peroxisome proliferator activated receptor alpha (PPARα), a transcription factor involved in fatty acid oxidation is implicated in the regulation of renal function. As both HIF-1α/PHD and PPARα contribute to the adaptive changes to altered oxygen tension, this study tested the hypothesis that PHD-induced renal adaptive response to HS is PPARα-dependent. METHODS: PPARα wild type (WT) and knock out (KO) mice were fed a low salt (LS) (0.03% NaCl) or a HS (8% NaCl) diet for 8 days and treated with hydralazine. PPARα and heme oxygenase (HO)-1 expression were evaluated in the kidney cortex and medulla. A 24-h urinary volume (UV), sodium excretion (UNaV), and nitrite excretion (UNOx V) were also determined. RESULTS: PHD1 expression was greater in the medulla as compared to the cortex of PPARα WT mice (p<0.05) fed with a LS (0.03% NaCl) diet. The HS diet (8% NaCl) downregulated PHD1 expression in the medulla (p<0.05) but not the cortex of WT mice whereas expression was downregulated in the cortex (p<0.05) and medulla (p<0.05) of KO mice. These changes were accompanied by HS-induced diuresis (p<0.05) and natriuresis (p<0.05) that were greater in WT mice (p<0.05). Similarly, UNOx V, index of renal nitric oxide synthase (NOS) activity or availability and heme oxygenase (HO)-1 expression was greater in WT (p<0.05) but unchanged in KO mice on HS diet. Hydralazine, a PHD inhibitor, did not affect diuresis or natriuresis in LS diet-fed WT or KO mice but both were increased (p<0.05) in HS diet-fed WT mice. Hydralazine also increased UNOx V (p<0.05) with no change in diuresis, natriuresis, or HO-1 expression in KO mice on HS diet. CONCLUSIONS: These data suggest that HS-induced PPARα-mediated downregulation of PHD1 is a novel pathway for PHD/HIF-1α transcriptional regulation for adaptive responses to promote renal function via downstream signaling involving NOS and HO.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180303
[Lr] Last revision date:180303
[St] Status:In-Process


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