HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD

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dc.contributor University of Helsinki, Department of Medicine en
dc.contributor.author Laitakari, Anna
dc.contributor.author Tapio, Joona
dc.contributor.author Mäkelä, Kari A.
dc.contributor.author Herzig, Karl-Heinz
dc.contributor.author Dengler, Franziska
dc.contributor.author Gylling, Helena
dc.contributor.author Walkinshaw, Gail
dc.contributor.author Myllyharju, Johanna
dc.contributor.author Dimova, Elitsa Y.
dc.contributor.author Serpi, Raisa
dc.contributor.author Koivunen, Peppi
dc.date.accessioned 2020-05-22T12:44:01Z
dc.date.available 2020-05-22T12:44:01Z
dc.date.issued 2020-05
dc.identifier.citation Laitakari , A , Tapio , J , Mäkelä , K A , Herzig , K-H , Dengler , F , Gylling , H , Walkinshaw , G , Myllyharju , J , Dimova , E Y , Serpi , R & Koivunen , P 2020 , ' HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD ' , Journal of Molecular Medicine , vol. 98 , no. 5 , pp. 719-731 . https://doi.org/10.1007/s00109-020-01903-0 en
dc.identifier.issn 0946-2716
dc.identifier.other PURE: 137549826
dc.identifier.other PURE UUID: b16601fc-c5da-469d-b432-61605d2bce42
dc.identifier.other WOS: 000526208600002
dc.identifier.uri http://hdl.handle.net/10138/315191
dc.description.abstract Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2(gt/gt)) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2(gt/gt) mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2(gt/gt) tissues, including the liver, was 15-35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2(gt/gt) small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2(gt/gt) mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD. Key messages center dot HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver. center dot HIF-P4H-2 inhibition downregulates hepatic lipogenesis. center dot Induced browning of WAT and increased thermogenesis can also mediate protection. center dot HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD. en
dc.format.extent 13
dc.language.iso eng
dc.relation.ispartof Journal of Molecular Medicine
dc.rights en
dc.subject Fructose en
dc.subject HIF en
dc.subject Hypoxia response en
dc.subject Metabolism en
dc.subject NAFLD en
dc.subject CHOLINE-DEFICIENT MODEL en
dc.subject FATTY LIVER-DISEASE en
dc.subject ADIPOSE-TISSUE en
dc.subject INSULIN-RESISTANCE en
dc.subject LIPID-METABOLISM en
dc.subject MOUSE MODEL en
dc.subject HYPOXIA en
dc.subject GLUCOSE en
dc.subject OBESITY en
dc.subject MICE en
dc.subject 1184 Genetics, developmental biology, physiology en
dc.subject 3121 Internal medicine en
dc.title HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD en
dc.type Article
dc.description.version Peer reviewed
dc.identifier.doi https://doi.org/10.1007/s00109-020-01903-0
dc.type.uri info:eu-repo/semantics/other
dc.type.uri info:eu-repo/semantics/publishedVersion
dc.contributor.pbl
dc.contributor.pbl
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