Figure 3.

Reprogramming of lipid metabolism under hypoxia. Hypoxia enhances lipogenesis by HIF-dependent modulation of proteins involved in fatty acid (FA) uptake, synthesis, storage and usage. Uptake of extracellular FA is promoted under hypoxia by activation of the transcription factor PPARγ and the increased expression of FABPs 3, 4 and 7. Endocytosis of lipoproteins is enhanced by the upregulation of LRP1 and VLDLR, while ceramide levels are increased by upregulation of NEU3. To maintain de novo FA synthesis under hypoxia, preservation of citrate levels and synthesis of acetyl-CoA is achieved by stimulation of reductive glutamine metabolism, mediated, at least in part, by induction of GLS1 and proteolysis of the OGDH2 subunit of the α-ketoglutarate dehydrogenase complex (αKGDH) by SIAH2. Adequate FA supply is further supported by activation of SREBP-1, which in turn upregulates the expression of FASN. To avoid lipotoxicity and/or replete lipid stores, FAs are converted to neutral triacylglycerols (TAGs), which are stored in lipid droplets (LDs). Formation of LDs under hypoxia is favored by the upregulation of the TAG biosynthesis pathway enzymes AGPAT2 and lipin-1, and the LD membrane proteins PLIN2 and HIG2. Finally, lipid accumulation under hypoxia is additionally supported by the inhibition of β-oxidation through downregulation of PGC-1α, CPT1A, PGC-1β, MCAD and LCAD. The proteins upregulated or activated under hypoxia are shown in red and the proteins downregulated or inhibited under hypoxia are shown in green. See text for details and references.