Exploring the Interplay between Bile Acids, High-Density Lipoproteins and Endothelial Cells in the Context of Obesity

Abstract

Obesity is a major health problem worldwide. Obesity is associated with many co-morbidities including hypertension, chronic inflammation, insulin resistance and dyslipidemia, all of which contribute to endothelial cell (EC) dysfunction, atherosclerosis and impaired glucose control. The overall rise in obesity and its comorbidities is a major driver of the increased incidence of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D). ECs are the first barrier between blood and body tissues, which act as gatekeepers of cardiovascular homeostasis. Indeed, EC-released vasoactive substances – in particular nitric oxide (NO) – regulate vasorelaxation, hemostasis, vascular permeability and modulate both acute and chronic immune responses to injuries. In light of its strong vasodilatory, anti-inflammatory and anti-oxidative properties, NO plays a central role in the maintenance of vascular health. EC homeostasis is influenced by paracrine and exocrine signals from several tissues and from the bloodstream. Among these, high-density lipoproteins (HDLs) play a pivotal role in the maintenance of EC homeostasis thanks to their ability to stimulate NO production, reduce EC inflammation, apoptosis and reactive oxygen species (ROS). It has been shown that obesity induces changes in HDL circulating levels, composition and subclass distribution. These changes cause a switch of HDL functionality from EC-protective particles towards EC dysfunction promoting. Metabolic activation, increased oxidative stress, reduced NO production, increased expression and release of pro-inflammatory molecules and production of extracellular vesicles represent the hallmarks of endothelial dysfunction. Gastric bypass - in particular Roux-en-Y gastric bypass (RYGB)- is the gold standard treatment for weight-loss in morbidly obese patients. Unlike many other weight-loss strategies, RYGB has been associated with rapid and (partially) body-weight independent improvements in obesity-induced inflammation, insulin resistance and CV risk. Our research group and others have observed that RYGB increases the concentration of bile acids (BAs) and gut peptides (e.g., glucagon-like peptide-1 (GLP-1)) in the systemic circulation, partially reverting obesity-induced impairment. Physiologically, 5% of BA escape the re-uptake from the liver and can be found in the bloodstream, therefore the endothelium is constantly exposed to a certain concentration of circulating BAs (from 2 µmol/L in fasting state to 15 µmol/L after a meal). BAs may directly target vascular ECs through BA-mediated activation of the Takeda G-protein Receptor 5 (TGR5) and Farnesoid X Receptor (FXR) receptors. Given their lipophilic nature, BAs are transported through the systemic circulation by plasma proteins. In physiological conditions, BAs are mostly bound to albumin. Nevertheless, 5-10% of the overall circulating BAs can be found bounded to lipoproteins, in particular HDLs. The increase in circulating BAs and the concomitant changes in BA-pool observed in patients with obesity after RYGB destabilise the BA-albumin ratio, thus increasing the binding of BAs with HDLs and rescuing HDL functionality by altering the obesity-induced dysfunctional HDL composition. BAs and HDLs may also act synergistically in promoting EC homeostasis after RYGB, therefore contributing to the observed improvements in CV risk. However, the exact role of BAs and the molecular mechanisms underlying the beneficial cardiovascular effects of bariatric surgery have not been completely identified yet. In this dissertation, the Candidate aims to contribute to further elucidating the effect of RYGB on CV risk by focusing on 1) investigating the effect of BAs and HDL-BAs on EC homeostasis and 2) identifying new prognostic markers able to predict cardio-metabolic RYGB outcome. In Chapter 1, the Candidate describes the intricate crosstalk between HDLs and ECs, focusing on the most important - but still underestimated - sex and gender differences that may impact this communication. In Chapter 2, the Candidate explores the effect of BAs and HDL-BAs on EC function under physiological and pro-apoptotic/pro-inflammatory conditions. To conclude, in Chapter 3, the Candidate and her colleagues propose the analysis of EC-derived extracellular vesicle levels and composition as a prognostic marker to predict the reduction in CV risk in patients with obesity undergoing RYGB.