Lipid Metabolism in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is distinguished by its sky-blue cytoplasm reflecting abundant lipid and glycogen deposits. Central to its pathogenesis is loss of function of the von Hippel-Lindau tumour suppressor, stabilising hypoxia-inducible factors (HIF1 and HIF2) and reprogramming cellular metabolism. Under HIF control, fatty acid uptake is enhanced and mitochondrial import of long-chain fatty acids is suppressed, diverting lipids into storage as lipid droplets. Concurrent activation of de novo lipogenesis and suppression of fatty acid β-oxidation fuel tumour growth, support redox balance, and buffer against lipotoxic stress under fluctuating oxygen levels. Key enzymes and pathways include carnitine palmitoyltransferase 1A (CPT1A), stearoyl-CoA desaturase (SCD1), fatty acid synthase (FASN) and lipid transporters such as scavenger receptor class B type I (SR-BI). This metabolic rewiring underpins phenotypic hallmarks of ccRCC, offers non-invasive imaging biomarkers and uncovers therapeutic vulnerabilities through targeted inhibition of lipid synthesis or modulation of lipid storage.

Research from Nature Portfolio

Recent investigations have demonstrated direct HIF-mediated repression of CPT1A, the rate-limiting enzyme for mitochondrial fatty acid import. Downregulation of CPT1A diminishes fatty acid oxidation and drives lipid droplet accumulation, which is essential for tumour formation and correlates with poor patient outcome. Complementing this, integrated lipidomic and transcriptomic profiling of ccRCC tissues has mapped a distinct lipid signature characterised by elevated cholesterol esters, triacylglycerols and ether-type phospholipids, alongside reduced polyunsaturated phospholipids. Transcriptome analysis revealed suppression of phosphatidylethanolamine synthesis pathways and upregulation of desaturases, underscoring coordinated control of lipid composition to favour tumour proliferation.

Lipid Metabolism in Clear Cell Renal Cell Carcinoma publication trend

The graph below shows the total number of articles in lipid metabolism in clear cell renal cell carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Hypoxia-inducible factors (HIF): Transcription factors stabilised by low oxygen that drive metabolic reprogramming in ccRCC.

Carnitine palmitoyltransferase 1A (CPT1A): Enzyme controlling mitochondrial uptake of long-chain fatty acids for β-oxidation.

Lipid droplets: Intracellular organelles storing neutral lipids that buffer fatty acid flux and support tumour survival.

De novo lipogenesis (DNL): Metabolic pathway synthesising fatty acids from acetyl-CoA, upregulated in ccRCC.

Fatty acid synthase (FASN): Key enzyme in DNL catalysing the formation of palmitate, often overexpressed in ccRCC.

References

1. GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT. Journal of Experimental & Clinical Cancer Research (2023).
2. The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling. Cell Death & Disease (2023).
3. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nature Communications (2017).
4. Lipidomic Signatures and Associated Transcriptomic Profiles of Clear Cell Renal Cell Carcinoma. Scientific Reports (2016).
5. Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative Dixon MRI. JCI Insight (2017).
6. Up-regulation of SR-BI promotes progression and serves as a prognostic biomarker in clear cell renal cell carcinoma. BMC Cancer (2018).