Ceramide and polyunsaturated phospholipids are strongly reduced in human hepatocellular carcinoma

• Polyunsaturated phospholipids are reduced in HCC tissues compared to adjacent tissues.
• Ceramide is markedly lower in HCC tissues than in non-tumorous liver.
• Type 2 diabetes does not modify HCC associated lipid changes.
• Lipid species changed in HCC do mostly not correlate with the respective serum levels.

Lipid composition affects membrane function, cell proliferation and cell death and is changed in cancer tissues. Hepatocellular carcinoma (HCC) is an aggressive cancer and this study aimed at a comprehensive characterization of hepatic and serum lipids in human HCC. Cholesteryl ester were higher in tumorous tissues (TT) compared to adjacent non-tumorous tissues (NT). Free cholesterol exerting cytotoxic effects was not changed. Phosphatidylethanolamine, -serine (PS) and -inositol but not phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) were reduced in HCC tissues. Saturated species mostly increased and polyunsaturated species were diminished in all of these phospholipids. Ceramide (Cer) was markedly reduced in HCC tissues and higher levels of sphingomyelin suggest impaired sphingomyelinase activity as one of the underlying mechanisms. Importantly, ceramide in NT increased in HCC stage T3. Ceramide released from hepatocytes attracts immune cells and a positive association of the macrophage specific receptor CD163 with NT ceramide was identified. HCC associated lipid changes did not differ in patients suffering from type 2 diabetes. Protein levels of p53 were induced in TT and negatively correlated with Cer d18:1/16:0 and PS 36:1. Of the lipid species changed in HCC tissues only TT Cer d18:1/16:0, Cer d18:1/24:1, PC 38:6 and LPC 22:6 correlated with the respective serum levels. Our study demonstrates a considerably altered hepatic lipidome in HCC tissues. Ceramide was markedly reduced in HCC tissues, and therefore, raising ceramide levels specifically in the tumor represents a reasonable therapeutic approach for the treatment of this malignancy.