University of Oulu

Tapio, J., Halmetoja, R., Dimova, E. Y., Mäki, J. M., Laitala, A., Walkinshaw, G., Myllyharju, J., Serpi, R., & Koivunen, P. (2022). Contribution of HIF-P4H isoenzyme inhibition to metabolism indicates major beneficial effects being conveyed by HIF-P4H-2 antagonism. Journal of Biological Chemistry, 298(8), 102222.

Contribution of HIF-P4H isoenzyme inhibition to metabolism indicates major beneficial effects being conveyed by HIF-P4H-2 antagonism

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Author: Tapio, Joona1; Halmetoja, Riikka1; Dimova, Elitsa Y.1;
Organizations: 1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
2FibroGen Inc, San Francisco, California, USA
3Faculty of Medicine, University of Oulu, Oulu, Finland
4Biobank Borealis of Northern Finland, Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5 MB)
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Language: English
Published: American Society for Biochemistry and Molecular Biology, 2022
Publish Date: 2023-02-22


Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases (HIF-P4Hs 1–3) are druggable targets in renal anemia, where pan-HIF-P4H inhibitors induce an erythropoietic response. Preclinical data suggest that HIF-P4Hs could also be therapeutic targets for treating metabolic dysfunction, although the contributions of HIF-P4H isoenzymes in various tissues to the metabolic phenotype are inadequately understood. Here, we used mouse lines that were gene-deficient for HIF-P4Hs 1 to 3 and two preclinical pan-HIF-P4H inhibitors to study the contributions of these isoenzymes to the anthropometric and metabolic outcome and HIF response. We show both inhibitors induced a HIF response in wildtype white adipose tissue (WAT), liver, and skeletal muscle and alleviated metabolic dysfunction during a 6-week treatment period, but they did not alter healthy metabolism. Our data indicate that HIF-P4H-1 contributed especially to skeletal muscle and WAT metabolism and that its loss lowered body weight and serum cholesterol levels upon aging. In addition, we found HIF-P4H-3 had effects on the liver and WAT and its loss increased body weight, adiposity, liver weight and triglyceride levels, WAT inflammation, and cholesterol levels and resulted in hyperglycemia and insulin resistance, especially during aging. Finally, we demonstrate HIF-P4H-2 affected all tissues studied; its inhibition lowered body and liver weight and serum cholesterol levels and improved glucose tolerance. We found very few HIF target metabolic mRNAs were regulated by the inhibition of three isoenzymes, thus suggesting a potential for selective therapeutic tractability. Altogether, these data provide specifications for the future development of HIF-P4H inhibitors for the treatment of metabolic diseases.

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Series: Journal of biological chemistry
ISSN: 0021-9258
ISSN-E: 1083-351X
ISSN-L: 0021-9258
Volume: 298
Issue: 8
Article number: 102222
DOI: 10.1016/j.jbc.2022.102222
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was supported by Academy of Finland grants 266719 and 308009 (P. K.), and 296498 (J. M.), Academy of Finland Center of Excellence 2012 to 2017 grants 251314 and 284605 (J. M.), and grants from the S. Jusélius Foundation (P. K. and J. M.) and the Jane and Aatos Erkko Foundation (P. K. and J. M.).
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)
284605 (Academy of Finland Funding decision)
Copyright information: © 2022 The Authors. This is an open access article under the CC BY license (