Detrimental Effect of Hypercholesterolemia on High-Density Lipoprotein Particle Remodeling in Pigs

Abstract

We demonstrate that hypercholesterolemia induces HDL lipidomic changes, losing phosphatidylcholine-lipid species and gaining cholesteryl esters, and proteomic changes, with losses in cardioprotective proteins. These remodeling changes shifted HDL particles toward a dysfunctional state.

Advances in HDL: Much More than Lipid Transporters

“…ApoA-I is synthesized in both the intestine and the liver and constitutes approximately 70% of HDL protein size. ApoA-II is only synthesized in the liver, represents approximately 20% of HDL protein, and is present on about two-thirds of HDL particles in humans [13,14]. Besides apoA -I and -II, HDLs express other apolipoproteins, which, in order of detection, include ApoC-III, ApoL1, ApoA-II, ApoE, ApoC-I, ApoC-II, and ApoM [15].…”

“…At a lipid level, more than 200 lipid species have been identified to constitute HDL particles [16]. These are generally classified as neutral hydrophobic lipids (cholesteryl esters and triglycerides present in the HDL core), and amphipathic lipids (free cholesterol or phospholipids mainly transported on the HDL surface) [13]. The HDL lipid composition is comprised of 35-50% of phospholipids, 5-10% of sphingolipids, 30-40% of cholesterol esters, 5-10% of free cholesterol, and 5-12% of triglyceride [16].…”

“…[86]. Moreover, the presence of cardiovascular risk factors, including hypercholesterolemia [13,60,87], obesity [88], diabetes type 1 and 2 [89,90], and even frequent exposure to pollution [91][92][93] or ethnicity have demonstrated to impact HDL properties and induce structural changes leading to variations in their subtypes profile. Altogether, these conditions may help explain the disappointing results observed in clinical trials aiming to increase HDL-c levels in secondary prevention.…”

“…Particularly, HDL particles formed under hypercholesterolemic conditions, as compared to HDL particles formed in a normocholesterolemic milieu, have lower levels of phosphatidylcholine-lipid species and higher levels of cholesteryl esters (i.e., mature HDL particles with lower membrane fluidity) and a lower cargo of several proteins with known cardioprotective functions, including ApoM and lipocalin retinol-binding protein-4. Interestingly, such adverse structural remodeling is associated with a marked reduction in HDL antioxidant and cholesterol efflux capacity and complete loss of HDL-related cardioprotection [13].…”

Cross-Talk between Lipoproteins and Inflammation: The Role of Microvesicles

“…On the other hand, high density lipoprotein (HDL) particles, when functionally capable, can exert the opposite effect by removing cholesterol from the circulation through the induction of reverse cholesterol transport, by protecting LDL and other proteins from oxidative damage [5], and by inhibiting monocyte production of inflammatory cytokines [6,7] and monocyte differentiation [8]. However, alterations in the HDL structure and function can render dysfunctional HDL particles that may exert deleterious effects in the CV system [9,10]. Inflammation plays a pivotal role in atherosclerotic plaque formation and instability by promoting endothelial cell activation, endothelial dysfunction, loss of integrity and lipid deposition in the intima and by impairing endothelial-repairing capacity [11].…”