Abstract
BackgroundDysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). The respective metabolic pathways affected in HCC can be identified using suitable experimental models. Mice injected with diethylnitrosamine (DEN) and fed a normal chow develop HCC. For the analysis of the pathophysiology of HCC in this model a comprehensive lipidomic analysis was performed.MethodsLipids were measured in tumor and non-tumorous tissues by direct flow injection analysis. Proteins with a role in lipid metabolism were analysed by immunoblot. Mann-Whitney U-test or paired Student´s t-test were used for data analysis.ResultsIntra-tumor lipid deposition is a characteristic of HCCs, and di- and triglycerides accumulated in the tumor tissues of the mice. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha, lipoprotein lipase and hepatic lipase protein were low in the tumors whereas proteins involved in de novo lipogenesis were not changed. Higher rates of de novo lipogenesis cause a shift towards saturated acyl chains, which did not occur in the murine HCC model. Besides, LDL-receptor protein and cholesteryl ester levels were higher in the murine HCC tissues. Ceramides are cytotoxic lipids and are low in human HCCs. Notably, ceramide levels increased in the murine tumors, and the simultaneous decline of sphingomyelins suggests that sphingomyelinases were involved herein. DEN is well described to induce the tumor suppressor protein p53 in the liver, and p53 was additionally upregulated in the tumors.ConclusionsCeramides mediate the anti-cancer effects of different chemotherapeutic drugs and restoration of ceramide levels was effective against HCC. High ceramide levels in the tumors makes the DEN injected mice an unsuitable model to study therapies targeting ceramide metabolism. This model is useful for investigating how tumors evade the cytotoxic effects of ceramides.
Highlights
Hepatocellular carcinoma is a hard-to-cure malignancy and the incidence has progressively increased over the last decades [1,2,3]
The cancer lipidome of hepatocellular carcinoma (HCC) patients has been analysed in a few studies so far [5]. These analyses described that triglycerides accumulated in human HCC tissues [23,24,25]
Lipoprotein lipase, hepatic lipase and PGC1alpha are downregulated in the tumors Activation of SREBP1c was comparable in non-tumor and tumor tissues of these mice (Supplementary Fig. 1a and [44])
Summary
Hepatocellular carcinoma is a hard-to-cure malignancy and the incidence has progressively increased over the last decades [1,2,3]. Various studies have documented a higher expression of enzymes involved in de novo lipogenesis in human HCC tissues [4,5,6,7,8]. Ablation of fatty acid synthase (FAS) prevented the proliferation of HCC cells invitro and delayed hepatocarcinogenesis in experimental models [9,10,11,12]. Further analysis showed that cholesterol biosynthesis was enhanced upon blockage of FAS in HCC cell lines and in the murine liver [10]. Ablation of fatty acid and cholesterol biosynthesis completely prevented tumorigenesis in the liver of a murine HCC model induced by loss of Phosphatase and Tensin homolog and overexpression of c-Met [10]. Dysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). For the analysis of the pathophysiology of HCC in this model a comprehensive lipidomic analysis was performed
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