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Metabolites 2017, 7(4), 49; https://doi.org/10.3390/metabo7040049

Specificities of Human Hepatocellular Carcinoma Developed on Non-Alcoholic Fatty Liver Disease in Absence of Cirrhosis Revealed by Tissue Extracts 1H-NMR Spectroscopy

1
Department of Digestive and Hepatobiliary Medecine, University Medical Hospital, F-63000 Clermont-Ferrand, France
2
INRA, Human Nutrition Unit, CRNH Auvergne, Clermont Auvergne University, F-63000 Clermont-Ferrand, France
3
Laboratory of Biophysics and Image Processing, Clermont Auvergne University, F-63000 Clermont-Ferrand, France
4
Department of Anatomo-pathology, University Medical Hospital, F-63000 Clermont-Ferrand, France
5
Team RMN-START, Clermont Auvergne University, F-63000 Clermont-Ferrand, France
6
Department of Clinical Research & Innovation, University Medical Hospital, F-63000 Clermont-Ferrand, France
7
Department of Digestive Surgery, University Medical Hospital, F-63000 Clermont-Ferrand, France
8
Department of Anatomo-pathology, University Medical Hospital, F-42000 Saint-Etienne, France
9
Department of Digestive Surgery, University Medical Hospital, F-42000 Saint-Etienne, France
10
UMR CNRS 6284, Clermont Auvergne University, F-63000 Clermont-Ferrand, France
*
Author to whom correspondence should be addressed.
Received: 29 August 2017 / Revised: 18 September 2017 / Accepted: 20 September 2017 / Published: 22 September 2017
(This article belongs to the Special Issue Metabolomics and Its Application in Human Diseases)
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Abstract

There is a rising incidence of non-alcoholic fatty liver disease (NAFLD) as well as of the frequency of Hepato-Cellular Carcinoma (HCC) associated with NAFLD. To seek for putative metabolic pathways specific of the NAFLD etiology, we performed comparative metabolomics between HCC associated with NAFLD and HCC associated with cirrhosis. The study included 28 pairs of HCC tissue versus distant Non-Tumoral Tissue (NTT) collected from patients undergoing hepatectomy. HCC was associated with cirrhosis (n = 9), normal liver (n = 6) and NAFLD (n = 13). Metabolomics was performed using 1H-NMR Spectroscopy on tissue extracts and combined to multivariate statistical analysis. In HCC compared to NTT, statistical models showed high levels of lactate and phosphocholine, and low level of glucose. Shared and Unique Structures (SUS) plots were performed to remove the impact of underlying disease on the metabolic profile of HCC. HCC-cirrhosis was characterized by high levels of β-hydroxybutyrate, tyrosine, phenylalanine and histidine whereas HCC-NAFLD was characterized by high levels of glutamine/glutamate. In addition, the overexpression glutamine/glutamate on HCC-NAFLD was confirmed by both Glutamine Synthetase (GS) immuno-staining and NMR-spectroscopy glutamine quantification. This study provides evidence of metabolic specificities of HCC associated with non-cirrhotic NAFLD versus HCC associated with cirrhosis. These alterations could suggest activation of glutamine synthetase pathway in HCC-NAFLD and mitochondrial dysfunction in HCC-cirrhosis, that may be part of specific carcinogenic processes. View Full-Text
Keywords: hepato-cellular carcinoma; 1H-NMR spectroscopy; metabolomics; cirrhosis; NAFLD; metabolites; biomarkers; glutamine synthetase hepato-cellular carcinoma; 1H-NMR spectroscopy; metabolomics; cirrhosis; NAFLD; metabolites; biomarkers; glutamine synthetase
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Teilhet, C.; Morvan, D.; Joubert-Zakeyh, J.; Biesse, A.-S.; Pereira, B.; Massoulier, S.; Dechelotte, P.; Pezet, D.; Buc, E.; Lamblin, G.; Peoc’h, M.; Porcheron, J.; Vasson, M.-P.; 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, 49.

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