| Objective Recent studies have shown that bile acids(BAs)modulate dysfunction of lipid metabolism via their signaling capabilities on various receptors.However,BAs alterations in response to the development of obesity and obesity related type 2 diabetes(T2DM)and their interactions with free fatty acids(FFAs)remain unclear.The aim of this study was to identify specific correlations between a set of specific BAs and a set of specific FFAs in association with metabolic disorders,evaluate their potential value as biomarkers for metabolic abnormalities in obese subjects,investigate the potential mechanisms of the regulation of BAs on FFAs and demonstrate the role of BA metabolism in obesity.Methods We performed targeted metabolomic measurements of serum BAs and FFAs profiles from 343 individuals participated in case-control study,including 199 healthy subjects,78 overweight or obese subjects,and 66 overweight or obese T2 DM subjects and a cohort of 38 obese patients with T2 DM who had undergone Roux-en-Y gastric bypass surgery(RYGB).Moreover,serum and liver samples of high fat diet induced obese mice with impaired glucose tolerance were also measured.Furthermore,gene expressions involved in FFA metabolism with treatment of BAs were analyzed in normal human liver L-02 cell lines.Also expressions of genes and proteins were analyzed in liver of high fat diet induced obese mice with impaired glucose tolerance.Lastly,we applied targeted metabolomics of BAs and 16 S rRNA gene sequencing of gut microbial populations to observe the composition of gut microbiome and alterations of phenotype of high fat diet induced obese mice with administration of GW4064 which induced the perturbation of BA metabolism.Results 1.In case-control study,deoxycholic acid species(DCA species)were significantly decreased in overweight or obese T2 DM subjects and had the negative correlation with clinical metabolic markers.While dihomo-γ-linolenic acid(DGLA)was markedly increased in serum of obese T2 DM and had strong and positive correlations with clinical metabolic markers,which was more capable of discriminating obese T2 DM subjects from obese.2.Compared with baseline,glucose tolerance and lipid profiles were significantly improved in obese T2 DM subjects at 12 months after RYGB.The level of DCA species was significantly increased and the level of DGLA was decreased at 12 months after RYGB in remission group.3.The level of DCA species was negatively correlated with DGLA.The ratio of DGLA to DCA species was significantly increased in obese T2 DM,while decreased in remission group 12 months after RYGB.This ratio was positively associated with many clinical metabolic markers.4.The level of DCA species was significantly decreased in serum and liver of high fat diet induced obese mice with imparied glucose tolerance,while the level of DGLA was increased in serum and liver of mice.The level of DCA species was negatively correlated with DGLA in serum and liver of mice.The ratio of DGLA to DCA species was significantly increased in both serum and liver of obese mice with imparied glucose tolerance and it had close correlation with biochemical markers.These results were coincided with clinical studies.5.DCA and its conjugated TDCA significantly inhibited the mRNA expression of fatty acid transport protein 5(FATP5),peroxisome proliferator activated receptor α(PPARα)and carnitine acyl transferase 1A(CPT1A),in the presence of DGLA in human liver L-02 cell lines.The mRNA and protein expressions of FATP5 were significantly increased in liver of high fat diet induced obese mice with impaired glucose tolerance.6.The synthetic farnesoid receptor X(FXR)agonist,GW4064 attenuated BA increase in the mice with high fat diet feeding,especially the levels of total bile acids and most of primary and secondary bile acids.In addition,the GW4064 supplementation fluctuated the gut microbiota.The alpha diversity was increased after GW4064 induced BA regulation.The relative abundance of Firmicutes and Proteobacteria was decreased,while Bacteroidetes,Tenericutes and Verrucomicrobia were significantly increased in GW4064 groups compared to high fat diet groups.Furthermore,changes in the gut microbiome induced by GW4064 were characterized by an increased relative abundance of Bacteroides,Prevotella,Allobaculum,Akkermansia and Lactobacillus which were beneficial and a decreased relative abundance of Oscillospira,Ruminococcus and Desulfovibrio which were harmful based on the taxonomy analysis at the genus level.Lastly,GW4064 administration inhibited obesity induced by high fat diet.Conclusions Our study demonstrates that dysregulated interplay between bile acid and fatty acid metabolism contributes to obesity related metabolic disorders.The ratio of DGLA to DCA species is an indication of unhealthy(T2DM)metabolic status and therefore a potential biomarker to identify metabolic abnormality in overweight or obese subjects.Our study suggests that targeting BA metabolism maybe a new therapeutic strategies for metabolic diseases. |
