Anna Laitakari, Teemu Ollonen, Thomas Kietzmann, Gail Walkinshaw, Daniela Mennerich, Valerio Izzi, Kirsi-Maria Haapasaari, Johanna Myllyharju, Raisa Serpi, Elitsa Y. Dimova, Peppi Koivunen, Systemic inactivation of hypoxia-inducible factor prolyl 4-hydroxylase 2 in mice protects from alcohol-induced fatty liver disease, Redox Biology, Volume 22, 2019, 101145, ISSN 2213-2317, https://doi.org/10.1016/j.redox.2019.101145
Systemic inactivation of hypoxia-inducible factor prolyl 4-hydroxylase 2 in mice protects from alcohol-induced fatty liver disease
|Author:||Laitakari, Anna1; Ollonen, Teemu1; Kietzmann, Thomas2;|
1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3FibroGen Inc., San Francisco, CA, USA
4Department of Pathology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 2.2 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020040914178
|Publish Date:|| 2020-04-09
Alcoholic fatty liver disease (AFLD) is a growing health problem for which no targeted therapy is available. We set out to study whether systemic inactivation of the main hypoxia-inducible factor prolyl 4-hydroxylase, HIF-P4H-2 (PHD2/EglN1), whose inactivation has been associated with protection against metabolic dysfunction, could ameliorate it. HIF-P4H-2-deficient and wild-type (WT) mice or HIF-P4H inhibitor-treated WT mice were subjected to an ethanol diet for 3–4 weeks and their metabolic health, liver and white adipose tissue (WAT) were analyzed. Primary hepatocytes from the mice were used to study cellular ethanol metabolism. The HIF-P4H-2-deficient mice retained a healthier metabolic profile, including less adiposity, better lipoprotein profile and restored insulin sensitivity, while on the ethanol diet than the WT. They also demonstrated protection from alcohol-induced steatosis and liver damage and had less WAT inflammation. In liver and WAT the expression of the key lipogenic and adipocytokine mRNAs, such as Fas and Ccl2, were downregulated, respectively. The upregulation of metabolic and antioxidant hypoxia-inducible factor (HIF) target genes, such as Slcs 16a1 and 16a3 and Gclc, respectively, and a higher catalytic activity of ALDH2 in the HIF-P4H-2-deficient hepatocytes improved handling of the toxic ethanol metabolites and oxidative stress. Pharmacological HIF-P4H inhibition in the WT mice phenocopied the protection against AFLD. Our data show that global genetic inactivation of HIF-P4H-2 and pharmacological HIF-P4H inhibition can protect mice from alcohol-induced steatosis and liver injury, suggesting that HIF-P4H inhibitors, now in clinical trials for renal anemia, could also be studied in randomized clinical trials for treatment of AFLD.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This study was supported by Academy of Finland grants 266719 and 308009 (PK), 296498 (JM), and 296027 (TK), the Academy of Finland Center of Excellence 2012–2017 grant 251314 (JM), and grants from the S. Jusélius Foundation (PK), the Emil Aaltonen Foundation (PK) and the Jane and Aatos Erkko Foundation (PK, TK, JM).
|Academy of Finland Grant Number:||
266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
296498 (Academy of Finland Funding decision)
296027 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).