Abstract
Background
The worldwide prevalences of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are estimated to range from 30 to 40 % and 5–17 %, respectively. Hepatocellular carcinoma (HCC) is primarily caused by hepatitis B infection, but retrospective data suggest that 4–29 % of NASH cases will progress to HCC. Currently the connection between NASH and HCC is unclear.
Aims
The purpose of this study was to identify changes in expression of HCC-related genes and metabolite profiles in NAFLD progression.
Methods
Transcriptomic and metabolomic datasets from human liver tissue representing NAFLD progression (normal, steatosis, NASH) were utilized and compared to published data for HCC.
Results
Genes involved in Wnt signaling were downregulated in NASH but have been reported to be upregulated in HCC. Extracellular matrix/angiogenesis genes were upregulated in NASH, similar to reports in HCC. Iron homeostasis is known to be perturbed in HCC and we observed downregulation of genes in this pathway. In the metabolomics analysis of hepatic NAFLD samples, several changes were opposite to what has been reported in plasma of HCC patients (lysine, phenylalanine, citrulline, creatine, creatinine, glycodeoxycholic acid, inosine, and alpha-ketoglutarate). In contrast, multiple acyl-lyso-phosphatidylcholine metabolites were downregulated in NASH livers, consistent with observations in HCC patient plasma.
Conclusions
These data indicate an overlap in the pathogenesis of NAFLD and HCC where several classes of HCC related genes and metabolites are altered in NAFLD. Importantly, Wnt signaling and several metabolites are different, thus implicating these genes and metabolites as mediators in the transition from NASH to HCC.
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Acknowledgments
We thank the National Institutes of Health-funded Liver Tissue Cell Distribution System liver tissue samples. In particular, we thank Marion Namenwirth (University of Minnesota), Melissa Thompson (Virginia Commonwealth University), and Dr. Stephen C. Strom and Kenneth Dorko (University of Pittsburgh). Support for this work was provided by the National Institute of Health Grant [DK068039], [ES006694], [HD062489]; the NIAID grant AI083927; the National Institute of Environmental Health Science Toxicology Training Grant [ES007091]; the Liver Tissue Cell Distribution System; National Institute of Health Contract [NO1-DK-7-00041-HHSN267200700004C]; and AVOZ50510513 from the Academy of Sciences of the Czech Republic.
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Clarke, J.D., Novak, P., Lake, A.D. et al. Characterization of Hepatocellular Carcinoma Related Genes and Metabolites in Human Nonalcoholic Fatty Liver Disease. Dig Dis Sci 59, 365–374 (2014). https://doi.org/10.1007/s10620-013-2873-9
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DOI: https://doi.org/10.1007/s10620-013-2873-9