Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs. F3F4). A non-targeted metabolomics strategy was applied. We analyzed 52 pairs of human HCC and adjacent non-tumoral tissues which included 26 HCC developed in severe fibrosis or cirrhosis (F3F4) and 26 in no or mild fibrosis (F0F1). Tissue extracts were analyzed using 1H-Nuclear Magnetic Resonance spectroscopy. An optimization evolutionary method based on genetic algorithm was used to identify discriminant metabolites. We identified 34 metabolites differentiating the two groups of NAFLD-HCC according to fibrosis level, allowing us to propose two metabolomics phenotypes of NAFLD-HCC. We showed that HCC-F0F1 mainly overexpressed choline derivatives and glutamine, whereas HCC-F3F4 were characterized by a decreased content of monounsaturated fatty acids (FA), an increase of saturated FA and an accumulation of branched amino acids. Comparing HCC-F0F1 and HCC-F3F4, differential expression levels of glucose, choline derivatives and phosphoethanolamine, monounsaturated FA, triacylglycerides were identified as specific signatures. Our metabolomics analysis of HCC tissues revealed for the first time two phenotypes of HCC developed in NAFLD according to fibrosis level. This study highlighted the impact of the underlying liver disease on metabolic reprogramming of the tumor.

The Emerging Role of Branched-Chain Amino Acids in Liver Diseases

“…A recent study found an increase in tissue BCAA level in HCC patients with severe fibrosis and cirrhosis. In 52 paired HCC tumor and nontumor tissues, BCAAs were found to be elevated in HCC tissue when compared with adjacent non-tumoral tissues [ 66 ]. The same finding was also found in another study with paired HCC tumor and nontumor tissues from 48 of their patients [ 67 ].…”

miR‐21‐5p promotes NASH‐related hepatocarcinogenesis

“…Furthermore, both hsa‐miR‐21‐5p and PPARA levels correlated with HCC tissue markers and related with worse prognosis, reinforcing the relevance of the hsa‐miR‐21‐5p/PPARα axis in HCC and in the progression of NAFLD towards cancer. In fact, NAFLD patients with high hsa‐miR‐21‐5p presented a hepatic metabolomic profile similar to that observed in patients with HCC and NAFLD‐HCC 41,42 . These metabolic alterations indicate activation of the Warburg effect, glycolysis, nucleotide synthesis and stimulation of pentose phosphate pathway, typically overactivated in HCC, as a way to accommodate the rapid cell division of tumour cells.…”

Molecular Changes Following Induction of Hepatocellular Carcinoma by Diethylnitrosamine and Thioacetamide, and Subsequent Treatment with Dioscorea membranacea Extract

“…Apart from the molecular aspects of hepatocarcinogenesis, the metabolic sequels of the genomic alterations also have their effect at the posttranslational level. A recent study in human [57] identified metabolites that were associated specifically with HCCs in a fibrotic or cirrhotic environment and that predominated in a pre-fibrotic environment. The majority of these changes in metabolite concentration are in all likelihood secondary to changes at the mRNA level, but choline, one of the metabolites, causes or aggravates fatty liver, while another, glutamine, is a key interorgan transporter of amino groups and a precursor to neurotransmitters.…”