Serum metabolomic profiling unveils distinct sex-related metabolic patterns in NAFLD

Abstract

ObjectiveObesity poses an increased risk for the onset of Nonalcoholic fatty liver disease (NAFLD). The influence of other factors, such as sex in the incidence and severity of this liver disease has not yet been fully elucidated. Thus, we aimed to identify the NAFLD serum metabolic signatures associated with sex in normal, overweight and obese patients and to associate the metabolite fluctuations across the increasing liver steatosis stages.Methods and resultsUsing nuclear magnetic resonance (NMR) serum samples of 210 NAFLD cases and control individuals diagnosed with liver U/S, our untargeted metabolomics enquiry provided a sex distinct metabolic bouquet. Increased levels of alanine, histidine and tyrosine are associated with severity of NAFLD in both men and women. Moreover, higher serum concentrations of valine, aspartic acid and mannose were positively associated with the progression of NAFLD among the male subjects, while a negative association was observed with the levels of creatine, phosphorylcholine and acetic acid. On the other hand, glucose was positively associated with the progression of NAFLD among the female subjects, while levels of threonine were negatively related. Fluctuations in ketone bodies acetoacetate and acetone were also observed among the female subjects probing a significant reduction in the circulatory levels of the former in NAFLD cases. A complex glycine response to hepatic steatosis of the female subjects deserves further investigation.ConclusionResults of this study aspire to address the paucity of data on sex differences regarding NAFLD pathogenesis. Targeted circulatory metabolome measurements could be used as diagnostic markers for the distinct stages of NAFLD in each sex and eventually aid in the development of novel sex-related therapeutic options.

Circulatory Metabolite Ratios as Indicators of Lifestyle Risk Factors Based on a Greek NAFLD Case–Control Study

“…This increase has been associated with hepatic fat accumulation in the early stages of MASLD. The tyrosine levels were positively related to NAFLD severity for both males and females in our recent study [ 24 ], as also observed in other studies [ 43 , 47 , 48 , 49 , 50 , 51 ]. Another study on the serum metabolome highlighted that elevated levels of BCAAs and aromatic amino acids are predictive biomarkers of T2D [ 52 ].…”

“…Serum NMR spectra were acquired using a Varian-600 MHz NMR spectrometer equipped with a 1 H{ 13 C/ 15 N} 5 mm PFG Automatable Triple Resonance probe at 25 °C, as previously described [ 24 ]. Briefly, the CPMG pulse sequence with presaturation water suppression was applied, collecting 128 transients with 64 K data points, with a relaxation delay of 5 s and an acquisition time of 4 s. Details of the serum sample pretreatment, including methanol (1:2 v / v ) extraction, centrifuging, as well as reconstitution in buffer, are also presented in [ 24 ].…”

“…The 1 H-NMR spectra process and metabolite annotation are also described in [ 24 ]. Briefly, MestreNova (v. 10.1) software was applied for the preprocess of the spectra (manual phase correction, automatic baseline correction and sinc apodization), normalization to the total area, binning with 0.001 ppm, and peak alignment against the superimposed spectrum.…”

Oxymatrine Alleviates High-Fat-High-Fructose-Induced Fatty Liver in Rats: Understanding the Molecular Mechanism Through an Untargeted Metabonomics Study

“…Elevated levels of histidine correlate with the severity of NAFLD. 35 Increased levels of its metabolite histamine lead to elevated levels of PARP-1 and IL-1β, as well as MAO-A, total MAO, CRP, and AST/ALT, causing liver injury. 36 In addition, histamine may regulate metabolic and inflammatory processes in other organs targeted by metabolic syndrome.…”