Systemic inactivation of hypoxia-inducible factor prolyl 4-hydroxylase 2 in mice protects from alcohol-induced fatty liver disease

Redox Biology
Anna LaitakariPeppi Koivunen

Abstract

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 ...Continue Reading

Citations

Jan 22, 2020·Annual Review of Immunology·Sean P ColganCormac T Taylor
Jan 25, 2020·Evidence-based Complementary and Alternative Medicine : ECAM·Chong PengKe-Er Huang
Feb 27, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Anna LaitakariPeppi Koivunen
May 15, 2019·International Journal of Molecular Sciences·Thomas Kietzmann
Apr 17, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Anna LaitakariPeppi Koivunen
Feb 13, 2021·Peptides·Thomas Kietzmann, Ville H Mäkelä
May 28, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Jenni MäättäPeppi Koivunen

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