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dc.date.accessioned2020-05-15T18:17:42Z
dc.date.available2020-05-15T18:17:42Z
dc.date.created2019-10-29T19:27:10Z
dc.date.issued2019
dc.identifier.citationLindquist, Carine Bjørndal, Bodil Bakke, Hege Gilbø Slettom, Grete Karoliussen, Marie Rustan, Arild Thoresen, G. Hege Skorve, Jon Nygård, Ottar Berge, Rolf Kristian . A mitochondria-targeted fatty acid analogue influences hepatic glucose metabolism and reduces the plasma insulin/glucose ratio in male Wistar rats. PLOS ONE. 2019, 14:e0222558(9), 1-17
dc.identifier.urihttp://hdl.handle.net/10852/75643
dc.description.abstractA fatty acid analogue, 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), was previously shown to have hypolipidemic effects in rats by targeting mitochondrial activity predominantly in liver. This study aimed to determine if 1-triple TTA could influence carbohydrate metabolism. Male Wistar rats were treated for three weeks with oral supplementation of 100 mg/kg body weight 1-triple TTA. Blood glucose and insulin levels, and liver carbohydrate metabolism gene expression and enzyme activities were determined. In addition, human myotubes and Huh7 liver cells were treated with 1-triple TTA, and glucose and fatty acid oxidation were determined. The level of plasma insulin was significantly reduced in 1-triple TTA-treated rats, resulting in a 32% reduction in the insulin/glucose ratio. The hepatic glucose and glycogen levels were lowered by 22% and 49%, respectively, compared to control. This was accompanied by lower hepatic gene expression of phosphenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, and Hnf4A, a regulator of gluconeogenesis. Gene expression of pyruvate kinase, catalysing the final step of glycolysis, was also reduced by 1-triple TTA. In addition, pyruvate dehydrogenase activity was reduced, accompanied by 10-15-fold increased gene expression of its regulator pyruvate dehydrogenase kinase 4 compared to control, suggesting reduced entry of pyruvate into the TCA cycle. Indeed, the NADPH-generating enzyme malic enzyme 1 (ME1) catalysing production of pyruvate from malate, was increased 13-fold at the gene expression level. Despite the decreased glycogen level, genes involved in glycogen synthesis were not affected in livers of 1-triple TTA treated rats. In contrast, the pentose phosphate pathway seemed to be increased as the hepatic gene expression of glucose-6-phosphate dehydrogenase (G6PD) was higher in 1-triple TTA treated rats compared to controls. In human Huh7 liver cells, but not in myotubes, 1-triple-TTA reduced glucose oxidation and induced fatty acid oxidation, in line with previous observations of increased hepatic mitochondrial palmitoyl-CoA oxidation in rats. Importantly, this work recognizes the liver as an important organ in glucose homeostasis. The mitochondrially targeted fatty acid analogue 1-triple TTA seemed to lower hepatic glucose and glycogen levels by inhibition of gluconeogenesis. This was also linked to a reduction in glucose oxidation accompanied by reduced PHD activity and stimulation of ME1 and G6PD, favouring a shift from glucose- to fatty acid oxidation. The reduced plasma insulin/glucose ratio indicate that 1-triple TTA may improve glucose tolerance in rats.en_US
dc.languageEN
dc.publisherPLOS
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleA mitochondria-targeted fatty acid analogue influences hepatic glucose metabolism and reduces the plasma insulin/glucose ratio in male Wistar ratsen_US
dc.typeJournal articleen_US
dc.creator.authorLindquist, Carine
dc.creator.authorBjørndal, Bodil
dc.creator.authorBakke, Hege Gilbø
dc.creator.authorSlettom, Grete
dc.creator.authorKaroliussen, Marie
dc.creator.authorRustan, Arild
dc.creator.authorThoresen, G. Hege
dc.creator.authorSkorve, Jon
dc.creator.authorNygård, Ottar
dc.creator.authorBerge, Rolf Kristian
cristin.unitcode185,15,23,30
cristin.unitnameFarmakologi og farmasøytisk biovitenskap
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1
dc.identifier.cristin1741860
dc.identifier.bibliographiccitationinfo:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=PLOS ONE&rft.volume=14:e0222558&rft.spage=1&rft.date=2019
dc.identifier.jtitlePLOS ONE
dc.identifier.volume14
dc.identifier.issue9
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0222558
dc.identifier.urnURN:NBN:no-78763
dc.type.documentTidsskriftartikkelen_US
dc.type.peerreviewedPeer reviewed
dc.source.issn1932-6203
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/75643/2/A%2Bmitochondria-targeted%2Bfatty%2Bacid%2Banalogue%2Binfluences%2Bhepatic%2Bglucose%2Bmetabolism%2Band%2Breduces%2Bthe%2Bplasma%2Binsulin_glucose%2Bratio%2Bin%2Bmale%2BWistar%2Brats.pdf
dc.type.versionPublishedVersion
cristin.articleide0222558


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