title: Liver fat deposition and mitochondrial dysfunction in morbid obesity: An approach combining metabolomics with liver imaging and histology.
abstract: OBJECTIVE
  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 (1)H 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 (1)H 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.
  
  
  CONCLUSIONS
  MRI is sufficient to stage NAFLD in obese patients and to assess the improvement after bariatric surgery. Other data were superfluous for this purpose.
authors.affiliation: 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.
authors.forename: Nahum
authors.initials: N
authors.lastname: Calvo
authors.affiliation: 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.
authors.forename: Raúl
authors.initials: R
authors.lastname: Beltrán-Debón
authors.affiliation: 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.
authors.forename: Esther
authors.initials: E
authors.lastname: Rodríguez-Gallego
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Hernández-Aguilera
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Guirro
authors.affiliation: 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.
authors.forename: Roger
authors.initials: R
authors.lastname: Mariné-Casadó
authors.affiliation: 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.
authors.forename: Lidón
authors.initials: L
authors.lastname: Millá
authors.affiliation: 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.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Alegret
authors.affiliation: 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.
authors.forename: Fàtima
authors.initials: F
authors.lastname: Sabench
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: del Castillo
authors.affiliation: 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.
authors.forename: María
authors.initials: M
authors.lastname: Vinaixa
authors.affiliation: 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.
authors.forename: Miguel Àngel
authors.initials: MÀ
authors.lastname: Rodríguez
authors.affiliation: 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Correig
authors.affiliation: 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.
authors.forename: Roberto
authors.initials: R
authors.lastname: García-Álvarez
authors.affiliation: 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.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.affiliation: 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Camps
authors.affiliation: 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.
authors.forename: Jorge
authors.initials: J
authors.lastname: Joven
mesh_terms: D000328:Adult; D050110:Bariatric Surgery; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000473:pathology; D009767:Obesity, Morbid / Q000150:complications* / Q000175:diagnosis / Q000601:surgery; D011237:Predictive Value of Tests; D011446:Prospective Studies; D066244:Proton Magnetic Resonance Spectroscopy; D012074:Remission Induction; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D013030:Spain; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D008055:Lipids
keywords: Fatty liver disease; Lipids; Magnetic resonance imaging; Magnetic resonance spectroscopy; Metabolomics; Mitochondrial function; Morbid obesity; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis