Nonalcoholic steatohepatitis (NASH) is a common
preneoplastic 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: (i) 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; (ii) 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 (iii) a NASH signature: reduced hepatic and circulating lignoceric and eicosapentaenoic
acids. Altogether, these results show the role of
lipid-modifying
enzymes converting
saturated fatty acids (SFA) to
monounsaturated fatty acids (MUFA) in HCC and the importance of an increased ratio of long chain n6-polyunsaturated
fatty acids over n3-polyunsaturated
fatty acids in NASH and HCC risk. They also highlight the relevance of the Pten-null model for studies related to NASH and HCC and show 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.