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Proteomic and lipidomic signatures of lipid metabolism in NASH-associated hepatocellular carcinoma

 Kyle Muir  ;  Antonious Hazim  ;  Ying He  ;  Marion Peyressatre  ;  Do-Young Kim  ;  Xiaoling Song  ;  Laura Beretta 
 CANCER RESEARCH, Vol.73(15) : 4722-4731, 2013 
Journal Title
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Animals ; Blotting, Western ; Carcinoma, Hepatocellular/etiology ; Carcinoma, Hepatocellular/metabolism ; Disease Models, Animal ; Fatty Liver/complications ; Fatty Liver/metabolism ; Humans ; Lipid Metabolism/physiology ; Liver Neoplasms/etiology ; Liver Neoplasms/metabolism ; Mice ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease ; PTEN Phosphohydrolase/deficiency ; PTEN Phosphohydrolase/genetics ; Polymerase Chain Reaction ; Proteome
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영)
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