Fig. 2.

In humans, formation of human hypoxia-inducible factors (HIFs) can occur only under hypoxia. Under normal conditions (normoxia), HIF-$\alpha$ is continuously degraded and cannot dimerize with HIF-$\beta$. Breakdown of HIF-$\alpha$ requires the action of prolyl hydroxylase isoenzymes and the subsequent attachment to the von Hippel Lindau protein, which labels HIF-$\alpha$ for degradation. HIF-$\alpha$ prolyl hydroxylase isoenzymes require oxygen to catalyze HIF-$\alpha$ hydroxylation. Therefore, hypoxia inhibits this reaction, impedes HIF-$\alpha$ degradation and allows the formation of functional HIF-1. Once activated, HIF-1$\alpha$ downregulates the expression of PPARG gene, which codes for peroxisome proliferatoractivated receptor gamma (PPAR-$\gamma$) and suppresses PPAR-$\gamma$ activity.