Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease

John D. Clarke, Petr Novak, April D. Lake, Petia Shipkova, Nelly Aranibar, Donald Robertson, Paul L. Severson, Michael D. Reily, Bernard W. Futscher, Lois D. Lehman-Mckeeman, Nathan J. Cherrington

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)365-374
Number of pages10
JournalDigestive diseases and sciences
Volume59
Issue number2
DOIs
StatePublished - Feb 1 2014

Keywords

  • Hepatocellular carcinoma
  • Metabolomics
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis

ASJC Scopus subject areas

  • Physiology
  • Gastroenterology

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    Clarke, J. D., Novak, P., Lake, A. D., Shipkova, P., Aranibar, N., Robertson, D., Severson, P. L., Reily, M. D., Futscher, B. W., Lehman-Mckeeman, L. D., & Cherrington, N. J. (2014). Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease. Digestive diseases and sciences, 59(2), 365-374. https://doi.org/10.1007/s10620-013-2873-9