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Lipid metabolism plays a basic role in renal physiology, especially in tubules. Hypoxia and hypoxia-induced factor (HIF) activation are common in renal diseases; however, the relationship between HIF and tubular lipid metabolism is poorly understood. Using prolyl hydroxylase inhibitor roxadustat (FG-4592), we verified and further explored the relationship between sustained HIF1α activation and lipid accumulation in cultured tubular cells. A transcriptome and chromatin immunoprecipitation sequencing analysis revealed that HIF1α directly regulates the expression of a number of genes possibly affecting lipid metabolism, including those associated with mitochondrial function. HIF1α activation suppressed fatty acid (FA) mobilization from lipid droplets (LDs) and extracellular FA uptake. Moreover, HIF1α decreased FA oxidation and ATP production. A lipidomics analysis showed that FG-4592 caused strong triglyceride (TG) accumulation and increased some types of phospholipids with polyunsaturated fatty acyl (PUFA) chains, as well as several proinflammatory lipids. Nevertheless, the overall FA level was maintained. Thus, our study indicated that HIF1α reduced the FA supply and utilization and reconstructed the composition of lipids in tubules, which is likely a part of hypoxic adaptation but could also be involved in pathological processes in the kidney.

Transcription-Based Multidimensional Regulation of Fatty Acid Metabolism by HIF1α in Renal Tubules