HDL as Bidirectional Lipid Vectors: Time for New Paradigms

Abstract

The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration.

Eicosapentaenoic and Docosahexaenoic Acid Supplementation Increases HDL Content in n-3 Fatty Acids and Improves Endothelial Function in Hypertriglyceridemic Patients

“…In this context, high-density lipoproteins (HDLs) have been described as lipoproteins with beneficial effects on endothelial function [ 12 , 13 , 14 ], probably associated with their EPA and DHA content [ 15 ]. HDLs are heterogeneous complexes of proteins and lipids that have been proposed to protect against cardiovascular disease through different mechanisms, including the reverse transport of cholesterol (RTC) [ 16 ]. It has also been described that HDLs induce endothelial nitric oxide synthase (eNOS) stability and phosphorylation, increasing its halftime and abundance [ 17 , 18 ].…”

“…Besides cholesterol efflux, we have recently demonstrated that HDLs also promote the influx of sphingomyelin and cholesterol, which improves endothelial cells in vitro [ 18 ]. Such observations suggest that HDLs are vectors that drive lipids to peripheral cells for structuring their membranes and other cellular functions [ 16 , 18 ]. Following this idea, we postulate that HDLs may carry n-3 fatty acids to endothelial cells in vivo, thus enhancing the functionality of this tissue.…”

HDL metabolism and functions impacting on cell cholesterol homeostasis are specifically altered in patients with abdominal aortic aneurysm

“…Interestingly, only within the AAA group serum CLC correlated directly with ABCG1-CEC and AD-CEC, mainly dependent on mature HDL, and inversely with ABCA1-CEC and CETP activity. The positive correlation of CLC with mature HDL particles suggests that this HDL subpopulation, besides being dysfunctional in terms of CEC in AAA, might even deliver cholesterol to cells ( 54 ). The inverse correlation of CLC with ABCA1-CEC and CETP activity found only in AAA is again consistent with the existence of a link between accelerated HDL metabolism, intracellular cholesterol, and aneurysm formation.…”

Inflammation and Oxidative Stress Induced by Obesity, Gestational Diabetes, and Preeclampsia in Pregnancy: Role of High-Density Lipoproteins as Vectors for Bioactive Compounds

“…the oxidation of the LDL Vascular function Modulation of endothelial nitric oxide synthase (eNOS) expression, leading to increased nitric oxide (NO) production and vasodilation ABCA1, SR-BI, S1PR, S1P, Apo M [170][171][172] These positive effects are explained by the structure and chemical composition of these particles. However, it has been shown that these lipoproteins can lose or reduce their cardioprotective capacity, giving rise to prooxidant, proinflammatory, and proatherogenic lipoproteins, contributing to the process of atherosclerosis; this phenomena has been termed "dysfunctional HDL" [173,174].…”