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. 2016 Apr 28;11(4):e0154601.
doi: 10.1371/journal.pone.0154601. eCollection 2016.

Increased Circulating Levels of Alpha-Ketoglutarate in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

Gemma Aragonès  1 , Teresa Auguet  1   2 , Alba Berlanga  1 , Esther Guiu-Jurado  1 , Salomé Martinez  3 , Sandra Armengol  1 , Fàtima Sabench  4 , Rosa Ras  5 , Mercè Hernandez  4 , Carmen Aguilar  1 , Josep Colom  6 , Joan Josep Sirvent  3 , Daniel Del Castillo  4 , Cristóbal Richart  1   2
Affiliations

Increased Circulating Levels of Alpha-Ketoglutarate in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

Gemma Aragonès et al. PLoS One. .

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, ranging from simple steatosis to cirrhosis. However, simple steatosis (SS) and steatohepatitis (NASH) cannot yet be distinguished by clinical or laboratory features. The aim of this study was to assess the relationship between alpha-ketoglutarate and the degrees of NAFLD in morbidly obese patients.

Materials and methods: We used a gas chromatography-quadruple time-of-flight-mass spectrometry analysis to quantify alpha-ketoglutarate in serum from normal-weight subjects (n = 30) and morbidly obese women (n = 97) with or without NAFLD.

Results: We found that serum levels of alpha-ketoglutarate were significantly higher in morbidly obese women than in normal-weight women. We showed that circulating levels of alpha-ketoglutarate were lower in lean controls and morbidly obese patients without NAFLD. We also found that alpha-ketoglutarate serum levels were higher in both SS and NASH than in normal liver of morbidly obese patients. However, there was no difference between SS and NASH. Moreover, we observed that circulating levels of alpha-ketoglutarate were associated with glucose metabolism parameters, lipid profile, hepatic enzymes and steatosis degree. In addition, diagnostic performance of alpha-ketoglutarate has been analyzed in NAFLD patients. The AUROC curves from patients with liver steatosis exhibited an acceptable clinical utility. Finally, we showed that the combination of biomarkers (AST, ALT and alpha-ketoglutarate) had the highest accuracy in diagnosing liver steatosis.

Conclusion: These findings suggest that alpha-ketoglutarate can determine the presence of non-alcoholic fatty liver in morbidly obese patients but it is not valid a biomarker for NASH.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Circulating levels of alpha-ketoglutarate in study cohort.
Circulating levels of alpha-ketoglutarate in normal-weight controls and morbidly obese women (A); in normal-weight controls, morbidly obese women (MO) without non-alcoholic fatty disease (NAFLD) and morbidly obese women (MO) with NAFLD (B); and in morbidly obese women according to the liver pathology (C). NL, morbidly obese women with normal liver; SS, morbidly obese women with simple steatosis; NASH, morbidly obese women with steatohepatitis. Results are shown as mean ± SD. p< 0.05 are considered statistically significant.
Fig 2
Fig 2. Significant correlations between alpha-ketoglutarate levels and anthropometrical and biochemical variables.
The strength of association between variables was calculated using Spearman’s r correlation test. BMI, body mass index; HbA1c, glycosylated hemoglobin; HOMA2-IR, homeostatic model assessment method-insulin resistance, HDL-C, high density lipoprotein cholesterol.
Fig 3
Fig 3. Serum alpha-ketoglutarate as a biomarker.
(A) Accuracy of alpha-ketoglutarate biomarker in population studied. Represent the performance for discriminating NAFLD, steatosis and NASH from non- diseased patients. The three values of optimum cutting were selected based on obtaining a first cutoff of high sensitivity (>90%), a second cutoff that included the best combination of sensitivity and specificity according to the Youden index and a third, which prioritized specificity (>90%) (B) Evaluation of a multimetabolite model as biomarkers of NAFLD by the receiver operator characteristic (AUROC) curves. AUROC, area under the curve of receiver operating characteristics; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LR+, positive likelihood ratio; LR-, negative likelihood ratio; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NPV, negative prespective value; PPV, positive prespective value.
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Publication types

Grants and funding

This study was supported by the Fondo de Investigación Sanitaria (FEDER, Grant Number PI13/00468 to Teresa Auguet), the Agència de Gestió d’Ajuts Universitaris de Recerca (AGAUR 2009 SGR 959 to Cristóbal Richart), the Grup de Recerca en Medicina Aplicada URV (2010 PFR-URV-B2-14 to Cristóbal Richart) and the Fundación Biociencia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.