P729The functional relevance of bile acids in the improvement of HDL-mediated endothelial protection after bariatric surgery

Abstract

Abstract Introduction Roux-en-Y gastric bypass (RYGB) reduces cardiovascular mortality. We showed that high density lipoproteins (HDL)-mediated vasoprotection is improved early after RYGB. Circulating BAs increase upon RYGB and contribute to the weight-loss independent metabolic improvements after surgery. Bile acids (BA) are signaling molecules increasingly recognized as regulators of cardiometabolic homeostasis. BAs circulate in the blood either free or bound to albumin and HDL. The signaling role of HDL-bound BAs (HDL-BAs) is unknown. Indeed, HDL may facilitate BA delivery directly to endothelial cells where BA may synergize with HDL to promote vasoprotection. Purpose We studied whether RYGB changes the composition of HDL-BA and whether HDL functional properties may be modulated by specific BA bound to HDL. Methods HDL were isolated by ultracentrifugation from 29 morbidly obese patients before and 1 year after RYGB. The HDL-BA composition was determined by liquid chromatography-mass spectrometry (LC/MS-MS) and HDL vasoprotective properties were evaluated ex-vivo in human aortic endothelial cells (HAEC). The size and abundance of HDL particles were determined by NMR spectroscopy in plasma. Results The increase in total BA concentrations observed in plasma 1 year after RYGB also translated into higher concentrations (up to 25%) of BA bound to HDL. Moreover, obesity-induced HDL dysfunction was reversed after surgery, as shown by improved HDL-mediated endothelial NO production, anti-apoptotic effects and cholesterol efflux capacity. The size function analyses showed a post-operative shift towards larger HDL. After RYGB there was a remodeling of BA bound to HDL, which are either agonists of the endothelial nuclear farnesoid X receptor (FXR), e.g. chenodeoxy-CA (CDCA), cholic acid (CA) or for the membrane TGR5 receptor, e.g. deoxy-CA (DCA). The composition-function analysis revealed that among all BA subclasses, the specific enrichment in CA and in CDCA bound to HDL correlated with an improved endothelial anti-apoptotic capacity of HDL (R −0.52, p=0.006 for CA-HDL and R −0.35, p=0.07 for CDCA-HDL). Further, the exogenous loading of CA onto healthy native HDL isolated from human serum significantly enhanced their endothelial anti-apoptotic function. In the case of obese, dysfunctional, pro-apoptotic HDL, exogenous CA loading was able to restore HDL anti-apoptotic function. Conclusion Exogenous loading of CA restored HDL anti-apoptotic function of HDL from obese patients mimicking the beneficial remodeling of BA bound to HDL observed after RYGB. These results suggest a crucial interaction between endothelial cells and BA in the improvement of HDL's vasoprotective properties. Acknowledgement/Funding Swiss national Science Foundation Ambizione and PRIMA grant to EO