TY - JOUR
T1 - Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease
AU - Clarke, John D.
AU - Novak, Petr
AU - Lake, April D.
AU - Shipkova, Petia
AU - Aranibar, Nelly
AU - Robertson, Donald
AU - Severson, Paul L.
AU - Reily, Michael D.
AU - Futscher, Bernard W.
AU - Lehman-Mckeeman, Lois D.
AU - Cherrington, Nathan J.
N1 - Funding Information:
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.
Funding Information:
Human liver tissue was acquired from the National Institutes of Health-funded Liver Tissue Cell Distribution System which was funded by NIH Contract #N01-DK-7-0004/HHSN267200700004C. Clinical and demographic information of these human liver samples has been described previously [13]. Tissues were collected post-mortem and preserved as either frozen or paraffin embedded tissue. The samples were diagnosed as normal (n = 19), steatotic (n = 10), NASH with fatty liver (n = 9), and NASH without fatty liver (n = 7). NAFLD activity scoring categorization was done by a Liver Tissue Cell Distribution System medical pathologist [15]. Steatosis was diagnosed by [10 % fat deposition within hepatocytes without inflammation or fibrosis. NASH with fatty liver was characterized by [5 % fat deposition with accompanied inflammation and fibrosis. NASH without fatty liver was distinguished by \5 % fat deposition and increased inflammation and fibrosis. Initially, all transcript and metabolite analyses were performed using the four diagnosis categories, but due to the lack of statistical differences between the two NASH categories, these two categories were combined creating three categories: normal, steatosis and NASH.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Hepatocellular carcinoma
KW - Metabolomics
KW - Nonalcoholic fatty liver disease
KW - Nonalcoholic steatohepatitis
UR - https://www.scopus.com/pages/publications/84896695216
UR - https://www.scopus.com/inward/citedby.url?scp=84896695216&partnerID=8YFLogxK
U2 - 10.1007/s10620-013-2873-9
DO - 10.1007/s10620-013-2873-9
M3 - Article
C2 - 24048683
AN - SCOPUS:84896695216
SN - 0163-2116
VL - 59
SP - 365
EP - 374
JO - Digestive diseases and sciences
JF - Digestive diseases and sciences
IS - 2
ER -