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Statements

Subject Item
n2:RIV%2F00216208%3A11160%2F14%3A10282278%21RIV15-MSM-11160___
rdf:type
n15:Vysledek skos:Concept
rdfs:seeAlso
http://onlinelibrary.wiley.com/doi/10.1111/bph.12585/full
dcterms:description
Background and Purpose The objective of this study was to determine how the AMPK activating antidiabetic drug metformin affects the major activator of hepatic gluconeogenesis, PPAR coactivator 1 (PGC-1) and liver functions regulated by PGC-1. Experimental Approach Mouse and human primary hepatocytes and mice in vivo were treated with metformin. Adenoviral overexpression, siRNA and reporter gene constructs were used for mechanistic studies. Key Results Metformin increased PGC-1 mRNA and protein expression in mouse primary hepatocytes. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) (another AMPK activator) had the opposite effect. Metformin also increased PGC-1 in human primary hepatocytes; this effect of metformin was abolished by AMPK inhibitor compound C and sirtuin 1 siRNA. AMPK overexpression by AMPK-Ad also increased PGC-1. Whereas metformin increased PGC-1, it down-regulated gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Furthermore, metformin attenuated the increase in PEPCK and G6Pase mRNAs induced by PGC-1 overexpression, but did not affect PGC-1-mediated induction of mitochondrial genes. Metformin down-regulated several key transcription factors that mediate the effect of PGC-1 on gluconeogenic genes including Kruppel-like factor 15, forkhead box protein O1 and hepatocyte NF 4, whereas it increased nuclear respiratory factor 1, which is involved in PGC-1-mediated regulation of mitochondrial proteins. Conclusions and Implications Down-regulation of PGC-1 is not necessary for suppression of gluconeogenic genes by metformin. Importantly, metformin selectively affects hepatic PGC-1-mediated gene regulation and prevents activation of gluconeogenesis, but does not influence its regulation of mitochondrial genes. These results identify selective modulation of hepatic PGC-1 functions as a novel mechanism involved in the therapeutic action of metformin. Background and Purpose The objective of this study was to determine how the AMPK activating antidiabetic drug metformin affects the major activator of hepatic gluconeogenesis, PPAR coactivator 1 (PGC-1) and liver functions regulated by PGC-1. Experimental Approach Mouse and human primary hepatocytes and mice in vivo were treated with metformin. Adenoviral overexpression, siRNA and reporter gene constructs were used for mechanistic studies. Key Results Metformin increased PGC-1 mRNA and protein expression in mouse primary hepatocytes. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) (another AMPK activator) had the opposite effect. Metformin also increased PGC-1 in human primary hepatocytes; this effect of metformin was abolished by AMPK inhibitor compound C and sirtuin 1 siRNA. AMPK overexpression by AMPK-Ad also increased PGC-1. Whereas metformin increased PGC-1, it down-regulated gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Furthermore, metformin attenuated the increase in PEPCK and G6Pase mRNAs induced by PGC-1 overexpression, but did not affect PGC-1-mediated induction of mitochondrial genes. Metformin down-regulated several key transcription factors that mediate the effect of PGC-1 on gluconeogenic genes including Kruppel-like factor 15, forkhead box protein O1 and hepatocyte NF 4, whereas it increased nuclear respiratory factor 1, which is involved in PGC-1-mediated regulation of mitochondrial proteins. Conclusions and Implications Down-regulation of PGC-1 is not necessary for suppression of gluconeogenic genes by metformin. Importantly, metformin selectively affects hepatic PGC-1-mediated gene regulation and prevents activation of gluconeogenesis, but does not influence its regulation of mitochondrial genes. These results identify selective modulation of hepatic PGC-1 functions as a novel mechanism involved in the therapeutic action of metformin.
dcterms:title
Metformin induces PGC-1a expression and selectively affects hepatic PGC-1a functions Metformin induces PGC-1a expression and selectively affects hepatic PGC-1a functions
skos:prefLabel
Metformin induces PGC-1a expression and selectively affects hepatic PGC-1a functions Metformin induces PGC-1a expression and selectively affects hepatic PGC-1a functions
skos:notation
RIV/00216208:11160/14:10282278!RIV15-MSM-11160___
n3:aktivita
n13:I n13:P
n3:aktivity
I, P(GAP303/12/0472)
n3:cisloPeriodika
9
n3:dodaniDat
n7:2015
n3:domaciTvurceVysledku
n18:4835549
n3:druhVysledku
n16:J
n3:duvernostUdaju
n11:S
n3:entitaPredkladatele
n14:predkladatel
n3:idSjednocenehoVysledku
28602
n3:idVysledku
RIV/00216208:11160/14:10282278
n3:jazykVysledku
n17:eng
n3:klicovaSlova
G6Pase; PEPCK; SIRT1; liver; gluconeogenesis; metformin; AMPK; PGC-1
n3:klicoveSlovo
n5:SIRT1 n5:metformin n5:PEPCK n5:PGC-1 n5:liver n5:gluconeogenesis n5:AMPK n5:G6Pase
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[230712AC3D2E]
n3:nazevZdroje
British Journal of Pharmacology
n3:obor
n20:FR
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
6
n3:projekt
n4:GAP303%2F12%2F0472
n3:rokUplatneniVysledku
n7:2014
n3:svazekPeriodika
171
n3:tvurceVysledku
Koulu, Markku Hakkola, Jukka Buler, Marcin Aatsinki, Sanna-Mari Pávek, Petr Salomaki, Henriikka
n3:wos
000334156100008
s:issn
0007-1188
s:numberOfPages
13
n19:doi
10.1111/bph.12585
n9:organizacniJednotka
11160