Functional lipidomics: palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism.

Lipidsare essential cellular componentsand energy sources of living organisms, and altered lipidcomposition is increasingly recognized as a signature of cancer. We performed lipidomicanalysis in a series of hepatocellular carcinoma (HCC) cells and identified over 1,700 intact lipidsoriginating from three major lipidcategories. Comparative lipidomicscreening revealed that 93 significantly changed lipidsand decreased palmitic acyl (C16:0)–containing glycerophospholipidswere positively associated with metastatic abilities of HCC cells. Furthermore, both in vitro and in vivo experiments demonstrated that C16:0 incubation specifically reduced malignant cell proliferation, impaired cell invasiveness, and suppressed tumor growth in mouse xenograft models. Biochemical experiments demonstrated that C16:0 treatment decreased cell membrane fluidityand limited glucose metabolism. A phosphoproteomicsapproach further revealed such C16:0 incubation attenuated phosphorylation levels of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) pathway proteins. Multiple reaction monitoring analysis of 443 lipidmolecules showed 8 reduced C16:0-containing lipidsout of total 10 altered lipidswhen cancer tissues were compared with adjacent nontumor tissues in a cohort of clinical HCC specimens (P < 0.05). Conclusion: These data collectively demonstrate the biomedical potential of using altered lipidmetabolism as a diagnostic marker for cancerous cells and open an opportunity for treating aggressive HCCs by targeting altered C16:0 metabolism. ( Hepatology2017;66:432–448).