Metabolomics-Based Study Of Metabolic Markers Associated With Central Obesity Promoting Hepatocellular Carcinogenesis In Patients With Chronic Hepatitis B On Antiviral Therapy

BackgroundSeveral previous studies have confirmed that central obesity is a risk factor of the development of kinds of cancer.Previous study has found that central obesity is an independent risk factor of hepatocellular carcinoma(HCC)in patients with chronic hepatitis B(CHB)who have achieved sustained viral suppression by receiving antiviral therapy,but the mechanisms by which central obesity promotes hepatocellular carcinogenesis are not yet clear.ObjectiveIn this study,we aimed to perform metabolomics analysis to explore the metabolic association between central obesity and HCC by comparing the differential metabolites between patients with and without HCC as well as patients with and without central obesity in order to suggest potential mechanisms by which central obesity promotes hepatocellular carcinogenesis.MethodsA total of 113 subjects were enrolled in this study,including 53 patients with CHB-related HCC and 60 matched CHB patients without HCC.Serum samples were collected from HCC patients at the time of being diagnosed with HCC(T1)and 18-24 months prior to diagnosis(T0),and for CHB patients,the serum samples were collected at the last visit(T1)and 18-24 months prior to the last visit(T0).Nontargeted metabolomics approach was used to characterize the subjects’ serum metabolic profile.Key metabolites were selected by comparing differential metabolites between groups(patients with progression to HCC vs.without progression to HCC,patients with HCC vs.without HCC,patients with central obesity vs.without central obesity).To finally identify metabolites involved in central obesity promoting hepatocellular carcinogenesis,we further constructed models for predicting HCC,analyzed the correlation between metabolites and clinical characteristics,analyzed the pathway enrichment of metabolites and compared metabolites abundance.Results120 differential metabolites were selected by comparing the metabolic profiles in patients with and without progression to HCC;163 differential metabolites were selected by comparing the metabolic profiles in patients with and without HCC;141 differential metabolites were selected by comparing the metabolic profiles in patients with and without central obesity.Finally,56 key metabolites were obtained by intersecting the differential metabolites in patients with and without central obesity and 224 metabolites obtained from the union of the differential metabolites in patients with and without progression to HCC and the differential metabolites in patients with and without HCC.For the above key metabolites,models for predicting HCC were constructed.The metabolites with p<0.1 in univariate logistic regression were used as variables to construct a multivariate logistic regression model,and a total of 7 metabolites were selected(AUC=0.826,sensitivity=83.02%,specificity=75.00%).5 metabolites were selected by using the Boruta algorithm and were further used to construct a gradient boost model.A total of eight metabolites involved in the mechanisms by which central obesity promotes hepatocellular carcinogenesis were finally selected in this study,including ethylmalonate,glycylvaline,thymol sulfate,5α-androstane-3β,7βdiol monosulfate(2),(R)-3-hydroxybutyrylcarnitine,1-palmitoyl-GPG(16:0),1,2,3benzenetriol sulfate(2),and fibrinopeptide B(1-13).Ethylmalonate and(R)-3-hydroxybutyrylcarnitine abundance were numerically higher in patients with HCC compared to patients without HCC at T0(ethylmalonate:-0.013 vs.0.090,p=0.063;(R)-3-hydroxybutyrylcarnitine:-0.203 vs.-0.075,p=0.089);and ethylmalonate and(R)-3-hydroxybutyrylcarnitine abundance were also numerically higher in patients with central obesity compared to patients without central obesity at T0(ethylmalonate:-0.037 vs.0.047,p=0.094;(R)-3hydroxybutyrylcarnitine:-0.160 vs.-0.086,p=0.195).ConclusionIn this study,we found eight metabolites that may be involved in the mechanisms by which central obesity promotes hepatocellular carcinogenesis in CHB patients receiving antiviral therapy based on non-targeted metabolomics approach.In particular,ethylmalonate and(R)-3-hydroxybutyrylcamitine may play an important role in the promotion of hepatocellular carcinogenesis.This study proposes a direction to explore the mechanisms of central obesity promoting hepatocellular carcinogenesis,and is expected to provide new strategies for liver cancer prevention and treatment in the future.