Combined Metabolomics and Genome-Wide Transcriptomics Analyses Show Multiple HIF1α-Induced Changes in Lipid Metabolism in Early Stage Clear Cell Renal Cell Carcinoma

The accumulation of lipids is a hallmark of human clear cell renal cell carcinoma (ccRCC). Advanced ccRCC tumors frequently show increased lipid biosynthesis, but the regulation of lipid metabolism in early stage ccRCC tumors has not been studied. Here, we performed combined transcriptomics and metabolomics on a previously characterized transgenic mouse model (TRAnsgenic Cancer of the Kidney, TRACK) of early stage ccRCC. We found that in TRACK kidneys, HIF1α activation increases transcripts of lipid receptors (Cd36, ACVRL1), lipid storage genes (Hilpda and Fabp7), and intracellular levels of essential fatty acids, including linoleic acid and linolenic acid. Feeding the TRACK mice a high-fat diet enhances lipid accumulation in the kidneys. These results show that HIF1α increases the uptake and storage of dietary lipids in this early stage ccRCC model. By then analyzing early stage human ccRCC specimens, we found similar increases in CD36 transcripts and increases in linoleic and linolenic acid relative to normal kidney samples. CD36 mRNA levels decreased, while FASN transcript levels increased with increasing ccRCC tumor stage. These results suggest that an increase in the lipid biosynthesis pathway in advanced ccRCC tumors may compensate for a decreased capacity of these advanced ccRCCs to scavenge extracellular lipids.