157 - The role of BA as signaling molecules and novel therapeutic targets to protect endothelial metabolism and function against obesity (ID 727)
Abstract
Background and Aims
Introduction: Bariatric surgery reduces cardiovascular morbidity and mortality. HDL-mediated endothelial-protection improves after bariatric surgery, namely RYGB. Circulating bile acids (BAs) increase upon RYGB and may promote its cardiometabolic benefits. BAs are novel regulators of cardiometabolic homeostasis, circulating free or bound to HDL. Aims. To study whether the composition of circulating BAs changes after RYGB and how BA synergize with HDL to protect the endothelium.
Methods
Methods: HDL were isolated by ultracentrifugation from 25 morbidly obese patients before and 1 year after RYGB. BA composition was assessed by liquid chromatography-mass spectrometry (LC/MS-MS). To test HDL-BA protective properties we used human aortic endothelial cells (HAEC).
Results
Results: 1 year after RYGB, BA concentration bound to HDL is increased (up to 25%) along with higher BA level in plasma. Obesity-induced HDL dysfunction was reversed post-RYGB, as shown by higher HDL-mediated NO production and lower apoptosis in HAEC. Higher amounts of cholic acid (CA) and chenodeoxy-CA (CDCA) are bound to HDL post-surgery and this correlates with HDL improved endothelial anti-apoptotic capacity. In obese HDL, exogenous CA loading improved HDL anti-apoptotic function, due to reduced phosphorylation of P38-MAPKinasethr180/tyr182, and downregulation of caspase-3 activity. Free CA and CDCA both improve endothelial metabolism in-part through down-regulation of glycolysis (extra-cellular acidification) and glucose uptake (radioactive 14C-glucose assay).
Conclusions
Conclusion: CA exogenous loading restored 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 EC and BA, with HDL facilitating BA endothelial protective functions.
