University of Oulu

Laitakari, A., Tapio, J., Mäkelä, K.A. et al. HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD. J Mol Med 98, 719–731 (2020).

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

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Author: Laitakari, Anna1; Tapio, Joona1; Mäkelä, Kari A.2;
Organizations: 1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Aapistie 7C, FIN-90014, Oulu, Finland
2Research Unit of Biomedicine, Biocenter Oulu, Medical Research Center and University Hospital, Oulu, Finland
3Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
4University of Leipzig, Leipzig, Germany
5Internal Medicine, University of Helsinki and Helsinki University Hospital, 00029 HUS, Helsinki, Finland
6FibroGen, Inc., San Francisco, CA, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 8.9 MB)
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Language: English
Published: Springer Nature, 2020
Publish Date: 2020-07-02


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-2gt/gt) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2gt/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-2gt/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-2gt/gt small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2gt/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.

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Series: Journal of molecular medicine
ISSN: 0946-2716
ISSN-E: 1432-1440
ISSN-L: 0946-2716
Volume: 98
Issue: 5
Pages: 719 - 731
DOI: 10.1007/s00109-020-01903-0
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This study was supported by the Academy of Finland grants 266719 and 308009 (PK), and 296498 (JM), the Academy of Finland Center of Excellence 2012–2017 grant 251314 (JM), and grants from the S. Jusélius Foundation (PK and JM), the Finnish Cancer Organization (PK), and the Jane and Aatos Erkko Foundation (PK and JM).
Academy of Finland Grant Number: 266719
Detailed Information: 266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
296498 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
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