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HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220983/ https://www.ncbi.nlm.nih.gov/pubmed/32296880 http://dx.doi.org/10.1007/s00109-020-01903-0 |
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author | Laitakari, Anna Tapio, Joona Mäkelä, Kari A. Herzig, Karl-Heinz Dengler, Franziska Gylling, Helena Walkinshaw, Gail Myllyharju, Johanna Dimova, Elitsa Y. Serpi, Raisa Koivunen, Peppi |
author_facet | Laitakari, Anna Tapio, Joona Mäkelä, Kari A. Herzig, Karl-Heinz Dengler, Franziska Gylling, Helena Walkinshaw, Gail Myllyharju, Johanna Dimova, Elitsa Y. Serpi, Raisa Koivunen, Peppi |
author_sort | Laitakari, Anna |
collection | PubMed |
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: • HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver. • HIF-P4H-2 inhibition downregulates hepatic lipogenesis. • Induced browning of WAT and increased thermogenesis can also mediate protection. • HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00109-020-01903-0) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7220983 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-72209832020-05-15 HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD Laitakari, Anna Tapio, Joona Mäkelä, Kari A. Herzig, Karl-Heinz Dengler, Franziska Gylling, Helena Walkinshaw, Gail Myllyharju, Johanna Dimova, Elitsa Y. Serpi, Raisa Koivunen, Peppi J Mol Med (Berl) Original Article 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: • HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver. • HIF-P4H-2 inhibition downregulates hepatic lipogenesis. • Induced browning of WAT and increased thermogenesis can also mediate protection. • HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00109-020-01903-0) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-04-15 2020 /pmc/articles/PMC7220983/ /pubmed/32296880 http://dx.doi.org/10.1007/s00109-020-01903-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Article Laitakari, Anna Tapio, Joona Mäkelä, Kari A. Herzig, Karl-Heinz Dengler, Franziska Gylling, Helena Walkinshaw, Gail Myllyharju, Johanna Dimova, Elitsa Y. Serpi, Raisa Koivunen, Peppi HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD |
title | HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD |
title_full | HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD |
title_fullStr | HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD |
title_full_unstemmed | HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD |
title_short | HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD |
title_sort | hif-p4h-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against nafld |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220983/ https://www.ncbi.nlm.nih.gov/pubmed/32296880 http://dx.doi.org/10.1007/s00109-020-01903-0 |
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