Research Activities

There is a growing incidence of non-alcoholic fatty liver disease (NAFLD) associated with an increased incidence of hepatocellular carcinoma (HCC) developing on NAFLD, which occurs in 40% of cases in the absence of cirrhosis or severe fibrosis. NAFLD is closely linked to obesity, type 2 diabetes, dyslipidemia, and insulin resistance and is considered the hepatic manifestation of metabolic syndrome. The metabolic pathways linking steatosis and steatohepatitis to HCC are understudied. There are no studies reporting the impact of fibrosis or cirrhosis on the metabolic profile of HCC developing on NAFLD (HCC-NAFLD). Our research aims to identify new biomarkers and propose metabolic pathways for HCC based on fibrosis stage (F0F1 versus F3F4).

Metabolic characteristics of HCC according to the level of fibrosis (F0F1 vs. F3F4)
Tissues were obtained from the French National Tumor Bank (CRB) Liver (n = 52), including 26 HCCs developed in patients with severe fibrosis or cirrhosis (F3F4) and 26 with no or mild fibrosis (F0F1). MR metabolomic analysis combined with an evolutionary optimization method (genetic algorithm, linear discriminant analysis, and cross-validation) revealed that HCCs developed in patients with NAFLD without fibrosis exhibit an increase in choline derivatives corresponding to an alteration in phospholipid membrane synthesis and an increase in glutamine levels. These metabolites, candidate biomarkers, suggest the activation of choline kinase and glutamine synthetase, respectively. In contrast, F3F4-HCCs developed on NAFLD with severe fibrosis or cirrhosis are characterized by an accumulation of branched-chain amino acids suggesting activation of the mTOR pathway. These metabolomic analyses suggest for the first time that there are two phenotypes of HCCs developed on NAFLD depending on the level of fibrosis. This study highlights the impact of the underlying pathology on the metabolic reprogramming of NAFLD-HCC.

Most notable publications

• LECUYER L, DALLE C, LYAN B, DEMIDEM A, ROSSARY A, VASSON MP, PETERA M, LAGREE M, FERREIRA T, CENTENO D, GALAN P, HERCBERG S, DESCHASAUX M, PARTULA V, SROUR B, LATINO-MARTEL P, KESSE-GUYOT E, DRUESNE PECOLLO N, DURAND S, PUJOS-GUILLOT E, TOUVIER M. Plasma metabolomic signatures associated with long-term breast cancer risk in the SU.VI.MAX prospective cohort. Cancer Epidemiol Biomarkers Prev. 2019      
• TEILHET C, REYNES C, SABATIER R, VASSON MP, ABERGEL A, DEMIDEM A. Human Hepatocellular Carcinoma metabolomic profile in Non Alcoholic Fatty Liver Disease (NAFLD) according to severity of fibrosis. Hepatol 2018, 80, 800-801.
• MORVAN D, DEMIDEM A. NMR metabolomics of fibroblasts with inherited mitochondrial Complex I mutation reveals treatment-reversible lipid and amino acid metabolism alterations. Metabolomics. 2018: 14: (5)
• TEILHET C, MORVAN D, JOUBERT-ZAKEYH J, BIESSE AS, PEREIRA B, MASSOULIER S, DECHELOTTE P, PEZET D, BUC E, LAMBLIN G, PEOC'H M, PORCHERON J, VASSON MP, ABERGEL A, DEMIDEM A. Specificities of human Hepatocellular Carcinoma developed on Non-Alcoholic Fatty Liver Disease in absence of cirrhosis revealed by tissue extracts ¹H-NMR Spectroscopy. Metabolites. 2017 ; 7, 4
• MORVAN D, DEMIDEM A. Metabolomics and transcriptomics demonstrate severe oxidative stress in both localized chemotherapy-treated and bystander tumors. Biochim Biophys Acta. 2014; 1840:1092-104                                                             

Other links

https://unh.clermont.hub.inrae.fr/notre-unite/les-equipes/ecrein