Thesis defence in the University of Oulu

Doctoral Candidate

Master of Science Anna Laitakari

Faculty and research unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, Hypoxia response

Field of study

Biochemistry and molecular medicine

Date and time of the thesis defence

16.8.2019 12:00

Place of the thesis defence

F101, Aapistie 7C, University of Oulu

Topic of the dissertation

Hypoxia-inducible factor prolyl 4-hydroxylase-2 in metabolism. A role in aging and in the pathogenesis of fatty liver diseases.

Opponent

Professor Sebastian Mueller, University of Heidelberg

Custos

Professor Peppi Karppinen, University of Oulu

Cellular oxygen sensor protects against liver diseases and tissue aging through metabolism

Liver diseases are becoming increasingly common throughout the world. Their exact molecular mechanisms are not yet fully understood, but the cause is often the nowadays common diet high in fat and sugar, which in addition to fatty liver results in metabolic disorders.

Oxygen is essential for all multicellular organisms and its reduced supply, hypoxia, triggers a response in cells to ensure oxygen delivery to tissues. Hypoxia has been shown to have both protective and harmful roles in various diseases. Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs) are oxygen sensors that regulate HIFs. Via hundreds of their target genes, HIFs have a role in regulating for example metabolism, angiogenesis and cell proliferation.

In this thesis, it was shown that mice with genetic HIF-P4H-2 inhibition were protected against the symptoms of alcoholic (AFLD) and non-alcoholic fatty liver disease (NAFLD): fatty liver, liver damage and disruptions of lipid and sugar metabolism, and additionally in NAFLD, obesity. In AFLD these mice demonstrated enhanced clearance of reactive oxygen species, whose accumulation is caused by alcohol metabolism. In NAFLD they showed reduced fructose uptake into tissues and enhanced heat production via browning of the white adipose tissue, which protected against weight gain.

In addition, it was shown in this thesis that the HIF-P4H-2 gene manipulation does not affect the life span of the mice or result in tumor formation, which hypoxia has previously been associated with. It was also shown that the HIF-P4H-2-deficient mice can maintain improved tissue health into senescence. These mice also had less inflammation and hepatocellular carcinomas.

Altogether, these studies show that long-term HIF-P4H-2 inhibition is harmless and offers potential for the development of novel therapeutics against liver diseases. The first pharmacologic compound inhibiting HIF-P4Hs was granted a marketing license for the treatment of kidney disease related anemia at the end of last year. The studies in this thesis show that the compounds also have potential for the treatment of liver diseases.

Last updated: 1.8.2019