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©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
Liver fat deposition and mitochondrial dysfunction in morbid obesity: An approach combining metabolomics with liver imaging and histology
Nahum Calvo, Raúl Beltrán-Debón, Esther Rodríguez-Gallego, Anna Hernández-Aguilera, Maria Guirro, Roger Mariné-Casadó, Lidón Millá, Josep M Alegret, Fàtima Sabench, Daniel del Castillo, María Vinaixa, Miguel Àngel Rodríguez, Xavier Correig, Roberto García-Álvarez, Javier A Menendez, Jordi Camps, Jorge Joven
Nahum Calvo, Raúl Beltrán-Debón, Esther Rodríguez-Gallego, Anna Hernández-Aguilera, Maria Guirro, Roger Mariné-Casadó, Lidón Millá, Josep M Alegret, Jordi Camps, Jorge Joven, Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, 43201 Reus, Spain
Fàtima Sabench, Daniel del Castillo, Servei de Cirurgia General i de l’Aparell Digestiu, Hospital Universitari de Sant Joan de Reus, Universitat Rovira i Virgili, 43201 Reus, Spain
María Vinaixa, Miguel Àngel Rodríguez, Xavier Correig, Metabolomics Platform, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, IISPV, Universitat Rovira i Virgili, 43007 Tarragona, Spain
Roberto García-Álvarez, Research and Collaborations, General Electric Healthcare, 78530 Buc, France
Javier A Menendez, Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona Biomedical Research Institute, 17007 Girona, Spain
Author contributions: Calvo N and Beltrán-Debón R contributed equally and were responsible for acquired data from MRI and MRS; all authors contributed to conception and design, acquisition of data, or analysis and interpretation of data; the article was written and edited by Joven J and Menendez JA and all authors revised and approved the final version; García-Álvarez R established the acquisition protocols in MRI and MRS and defined the methods of analysis; Sabench F and del Castillo D were responsible for the correct management of the participants; and Vinaixa M, Rodríguez MA and Correig X analysed by 1H-NMR the metabolites extracted in liver biopsies.
Supported by Universitat Rovira I Virgili and the Hospital de Sant Joan de Reus; Some aspects have been funded by grants from the Carlos III Health Institute, Madrid, Spain and the European Fund for Regional Development, No. PI08/1381 and No. PI11/00130.
Ethics approval: The local ethics committee, which acts as the institutional review board of the Hospital de Sant Joan de Reus.
Clinical trial registration: EPINOLS/12-03-29/3proj6; OBESPAD/14-07-31/7proj3.
Informed consent: The study protocol and procedures were approved, and written informed consent was obtained from the participants.
Conflict-of-interest: The authors declare that there are no conflicts of interest associated with this manuscript.
Data sharing: All data associated with this manuscript, conveniently anonymized, are available under request from the corresponding author, who takes responsibility for the integrity and the accuracy of data analysis.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Jorge Joven, MD, PhD, Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, c/ Sant Llorenç 21, 43201 Reus, Spain.
jorge.joven@urv.cat
Telephone: +34-977-310300 Fax: +34-977-59386
Received: November 27, 2014
Peer-review started: November 28, 2014
First decision: December 26, 2014
Revised: January 20, 2015
Accepted: February 12, 2015
Article in press: February 13, 2015
Published online: June 28, 2015
Processing time: 213 Days and 18 Hours
AIM: To explore the usefulness of magnetic resonance imaging (MRI) and spectroscopy (MRS) for assessment of non-alcoholic fat liver disease (NAFLD) as compared with liver histological and metabolomics findings.
METHODS: Patients undergoing bariatric surgery following procedures involved in laparoscopic sleeve gastrectomy were recruited as a model of obesity-induced NAFLD in an observational, prospective, single-site, cross-sectional study with a pre-set duration of 1 year. Relevant data were obtained prospectively and surrogates for inflammation, oxidative stress and lipid and glucose metabolism were obtained through standard laboratory measurements. To provide reliable data from MRI and MRS, novel procedures were designed to limit sampling variability and other sources of error using a 1.5T Signa HDx scanner and protocols acquired from the 3D or 2D Fat SAT FIESTA prescription manager. We used our previously described 1H NMR-based metabolomics assays. Data were obtained immediately before surgery and after a 12-mo period including histology of the liver and measurement of metabolites. Values from 1H NMR spectra obtained after surgery were omitted due to technical limitations.
RESULTS: MRI data showed excellent correlation with the concentration of liver triglycerides, other hepatic lipid components and the histological assessment, which excluded the presence of non-alcoholic steatohepatitis (NASH). MRI was sufficient to follow up NAFLD in obese patients undergoing bariatric surgery and data suggest usefulness in other clinical situations. The information provided by MRS replicated that obtained by MRI using the -CH3 peak (0.9 ppm), the -CH2- peak (1.3 ppm, mostly triglyceride) and the
-CH=CH- peak (2.2 ppm). No patient depicted NASH. After surgery all patients significantly decreased their body weight and steatosis was virtually absent even in patients with previous severe disease. Improvement was also observed in the serum concentrations of selected variables. The most relevant findings using metabolomics indicate increased levels of triglyceride and monounsaturated fatty acids in severe steatosis but those results were accompanied by a significant depletion of diglycerides, polyunsaturated fatty acids, glucose-6-phosphate and the ATP/AMP ratio. Combined data indicated the coordinated action on mitochondrial fat oxidation and glucose transport activity and may support the consideration of NAFLD as a likely mitochondrial disease. This concept may help to explain the dissociation between excess lipid storage in adipose tissue and NAFLD and may direct the search for plasma biomarkers and novel therapeutic strategies. A limitation of our study is that data were obtained in a relatively low number of patients.
CONCLUSION: MRI is sufficient to stage NAFLD in obese patients and to assess the improvement after bariatric surgery. Other data were superfluous for this purpose.
Core tip: Despite remaining obese, non-alcoholic fatty liver disease (NAFLD) regressed in patients undergoing bariatric surgery. Magnetic resonance imaging was sufficient to assess these findings and spectroscopy and measurement of liver fat content were superfluous for this purpose. Patients were free of hepatocyte ballooning or fibrosis and results may limit further the indication for liver biopsy to patients with known factors affecting the progression of liver disease. Additional information on the dissociation between lipid storage in adipose tissue and NAFLD suggests the presence of mitochondrial and inflammatory disease and may focus on the unmet need for plasma biomarkers of circulating metabolites produced during altered cellular fatty oxidation and glycolysis.
