Fatty acids accumulation in intrahepatic cholangiocarcinoma-derived tissue and sera

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary hepatic malignancy. Lipids are crucial for cell survival as components of biological membranes, energy suppliers and bioactive mediators. However, information on the iCCA lipidome profile is still lacking. Fatty acid (FA) synthesis is downregulated in iCCA while active uptake by specific transporters is enhanced, even though conflicting data exist on the mechanism of FA accumulation. Proliferation of CCA cell lines rely on lipid uptake to fuel FA catabolism and to promote FA storage in lipid droplets (LD) as neutral lipids. In this study we investigated the iCCA lipidome in paired iCCA and non¬tumour (NT) liver tissue and serum from iCCA patients, focusing on fatty acid metabolism. Lipid profile characterization of serum, surgically resected iCCA specimens and NT tissue was analyzed by LC¬MS/MS. In iCCA specimens and NT tissue, gene and protein expression were analysed by qPCR and WB analysis. The untargeted lipidome profile showed a clear¬cut separation between iCCA and NT tissues as well as between iCCA and HC sera. Indeed, FA accumulated both in iCCA tissue and patients’ sera. Expression of Acetyl¬CoA Carboxylase Alpha ACACA, the rate¬limiting enzyme of de novo lipogenesis, was higher in iCCA tissue than in NT tissue. FABP5 membrane¬associated transporter expression was unchanged; conversely, FABP4 and CD36 gene expression was down¬regulated in iCCA tissue. Several species of phospholipids and sphingolipids, the main components of plasma membranes, were upregulated in iCCA compared with NT tissues. This result was also confirmed by an in¬vitro metabolic labelling using deuterated palmitic acid. These findings suggest that FA accumulation could promote iCCA aggressiveness by supporting membrane biogenesis and generation of bioactive lipids. Differences in lipidome serum profile between iCCA patients and HC suggest a mean to identify individuals with iCCA by liquid biopsy.