Role of HIF-P4H inhibition and hemoglobin levels in metabolic diseases

Human survival relies on an adequate oxygen (O2) supply. Hemoglobin (Hb) is the main carrier of O2 in the circulatory system and its levels directly affect tissue oxygenation. When O2 levels decrease, a state of hypoxia occurs. Under hypoxia, a systemic response mechanism activates, increasing O2 supply and decreasing O2 demand. The response is regulated by the hypoxia-inducible factor (HIF) which targets genes in various pathways including energy metabolism. HIF is governed by O2-dependent HIF prolyl 4-hydroxylases (HIF-P4Hs 1-3), and inhibitors of these enzymes are currently used to treat renal anemia. Lower serum cholesterol levels have been reported in patients receiving HIF-P4H inhibitors.
To study the roles of each HIF-P4H isoenzyme in metabolism, we used two pan HIF-P4H inhibitors in wild-type (WT) and HIF-P4H deficient mice. Both inhibitors improved the metabolic profile of WT mice in a dose-dependent and safe manner. HIF-P4H-1 loss lowered body weight and cholesterol levels upon aging while HIF-P4H-3 loss led to an adverse metabolic profile. HIF-P4H-2 deficiency promoted metabolic health, protecting from non-alcoholic fatty liver disease via increased browning of white adipose tissue (WAT) and consequent thermogenesis, and by enhanced fructose metabolism in the intestine. Regulation of HIF target mRNAs was isoenzyme-specific, very few requiring inhibition by all three isoenzymes.
Using the normal variation in Hb levels as a surrogate measure for hypoxia, we explored how Hb levels relate to metabolic health in mice and humans, and used Mendelian randomization (MR) to evaluate causality. Lower Hb levels associated with a healthier metabolic profile and higher Hb levels with an adverse one. Additionally, higher Hb levels associated with development of type 2 diabetes, an increased risk for liver fat accumulation and with both total and cardiovascular-related mortalities. Moreover, expression of key HIF target genes associated with lower systolic blood pressure in MR analyses and healthier body composition in mice. Lastly, venesection altered Hb levels and metabolic parameters in mice.
The results present selective inhibition of isoenzyme 2, or 1/2, as a novel therapeutic option for metabolic diseases. Additionally, low-end normal Hb levels present as metabolically favorable, whereas high Hb levels increase the risk for developing metabolic diseases.