Obesity-Dependent Metabolic Signatures Associated with Nonalcoholic Fatty Liver Disease Progression

被引：181

作者：

Barr, J. ^{[2
]}

Caballeria, J. ^{[3
]}

Martinez-Arranz, I. ^{[2
]}

Dominguez-Diez, A. ^{[4
]}

Alonso, C. ^{[2
]}

Muntane, J. ^{[5
,6
]}

Perez-Cormenzana, M. ^{[2
]}

Garcia-Monzon, C. ^{[7
]}

Mayo, R. ^{[2
]}

Martin-Duce, A. ^{[8
]}

Romero-Gomez, M. ^{[9
]}

Lo Iacono, O. ^{[10
]}

Tordjman, J. ^{[11
,12
,13
]}

Andrade, R. J. ^{[14
]}

Perez-Carreras, M. ^{[15
]}

Le Marchand-Brustel, Y. ^{[16
]}

Tian, A. ^{[16
]}

Fernandez-Escalante, C. ^{[4
]}

Arevalo, E. ^{[5
,6
]}

Garcia-Unzueta, M. ^{[4
]}

Clement, K. ^{[11
,12
,13
]}

Crespo, J. ^{[4
]}

Gual, P. ^{[16
]}

Gomez-Fleitas, M. ^{[4
]}

Martinez-Chantar, M. L. ^{[1
]}

Castro, A. ^{[2
]}

Lu, S. C. ^{[17
]}

Vazquez-Chantada, M. ^{[2
]}

Mato, J. M. ^{[1
]}

机构：

[1] CIBERehd, CIC BioGUNE, Derio 48160, Bizkaia, Spain

[2] OWL, Derio, Bizkaia, Spain

[3] Hosp Clin Barcelona, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Liver Unit, Inst Invest Biomed August Pi Sunyer IDIBAPS, Barcelona, Spain

[4] Univ Cantabria, Hosp Univ Marques Valdecilla, Serv Anal Clin, Serv Cirugia Gen,Serv Aparato Digest, E-39005 Santander, Spain

[5] Reina Sofia Univ Hosp, Liver Res Unit, Surg Dept, IMIBIC, Cordoba, Spain

[6] CIBERehd, Inst Salud Carlos III, Madrid, Spain

[7] Univ Hosp Santa Cristina, CIBERehd, Inst Invest Sanit Princesa, Liver Res Unit, Madrid, Spain

[8] Univ Alcala de Henares, Hosp Univ Principe Asturias, Dept Enfermeria, Madrid, Spain

[9] Univ Seville, CIBERehd, Hosp Univ Nuestra Senora Valme, UG MQ Enf Digest, Seville, Spain

[10] Hosp Tajo, Secc Aparato Digest, Aranjuez, Spain

[11] Hop La Pitie Salpetriere, ICAN Inst Cardiometab & Nutr, Paris, France

[12] INSERM, U872, Paris, France

[13] Univ Paris 06, Ctr Rech Cordeliers, UMR S 872, Paris, France

[14] Hosp Clin Virgen Victoria, Hepatol Sect, CIBERehd, Malaga, Spain

[15] Hosp Univ 12 Octubre, Madrid, Spain

[16] Univ Nice Sophia Antipolis, INSERM, U895,Ctr Hosp Univ Nice, Team 8 Hepat Complicat Obesity,Fac Med,Digest Ctr, Nice, France

[17] Univ So Calif, Div Gastrointestinal & Liver Dis, USC Res Ctr Liver Dis,Keck Sch Med, So Calif Res Ctr Alcohol Liver & Pancreat Dis & C, Los Angeles, CA 90033 USA

来源：

JOURNAL OF PROTEOME RESEARCH | 2012年 / 11卷 / 04期

关键词：

NAFLD; steatosis; NASH; metabolomics; biomarkers; LIQUID-CHROMATOGRAPHY; INSULIN-RESISTANCE; HEPATIC STEATOSIS; MOUSE MODEL; STEATOHEPATITIS; ACIDS; SUSCEPTIBILITY; LIPOGENESIS; BIOPSY; PLASMA;

D O I：

10.1021/pr201223p

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n = 90) or diagnosed with NAFLD (steatosis, n = 246; NASH, n = 131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.

引用

页码：2521 / 2532

页数：12

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