Proteomic and lipidomic signatures of lipid metabolism in NASH-associated hepatocellular carcinoma
Menée à l'aide d'un modèle murin de stéatose hépatique non alcoolique (SHNA), cette étude identifie des biomarqueurs du métabolisme lipidique susceptibles d'être utilisés pour l'évaluation du risque de carcinome hépatocellulaire chez les patients atteints d'une SHNA
Non-alcoholic steatohepatitis (NASH) is a common pre-neoplastic condition of hepatocellular carcinoma (HCC). Mice with hepatocytic deletion of Pten develop NASH and HCC later in life. This model is highly valuable for studies aimed at identifying the molecular mechanism by which metabolic disorders contribute to tumor development. We applied proteomic and lipidomic profiling approaches to Pten null NASH liver and tumors. Circulating fatty acid composition was also characterized in these mice. The relevance to human NASH and HCC was further validated. This integrative proteomic and lipidomic study from mouse to human and from liver to blood, identified the following disease signatures: 1- an HCC signature: upregulated hepatic scd1/scd2, fads2 and acsl5:acsl1 ratio, elevated vaccenic and erucic acids and reduced margaric and linoleic acids in both liver and plasma; 2- a NASH signature that correlates with tumor burden: upregulated hepatic elovl6, elevated oleic, adrenic and osbond acids and reduced cervonic acid in liver and plasma; and 3- a NASH signature: reduced hepatic and circulating lignoceric and eicosapentaenoic acids. Altogether, these results demonstrate the role of lipid-modifying enzymes converting SFAs to MUFAs in HCC and the importance of an increased ratio of long chain n6-PUFAs over n3-PUFAs in NASH and HCC risk. They also highlight the relevance of the Pten null model for studies related to NASH and HCC and demonstrate that circulating lipid metabolome provides a direct read of lipid changes in the liver. Most importantly, novel candidate targets for HCC diagnosis, therapy, risk assessment and prevention were identified.
Cancer Research , résumé, 2013