HDL Dysfunctionality: Clinical Relevance of Quality Rather Than Quantity

Abstract

High-density lipoproteins (HDLs) represent a class of lipoproteins very heterogeneous in structure, composition, and biological functions, which carry out reverse cholesterol transport, antioxidant, anti-inflammatory, antithrombotic, and vasodilator actions. Despite the evidence suggesting a clear inverse relationship between HDL cholesterol (HDL-c) concentration and the risk for cardiovascular disease, plasma HDL cholesterol levels do not predict the functionality and composition of HDLs. The importance of defining both the amount of cholesterol transported and lipoprotein functionality has recently been highlighted. Indeed, different clinical conditions such as obesity, diabetes mellitus type 2 (T2DM), and cardiovascular disease (CVD) can alter the HDL functionality, converting normal HDLs into dysfunctional ones, undergoing structural changes, and exhibiting proinflammatory, pro-oxidant, prothrombotic, and proapoptotic properties. The aim of the current review is to summarize the actual knowledge concerning the physical–chemical alteration of HDLs related to their functions, which have been found to be relevant in several pathological conditions associated with systemic inflammation and oxidative stress.

Genetic Evidence for a Causal Relationship between Hyperlipidemia and Type 2 Diabetes in Mice

“…Its positive correlation with plasma glucose levels suggests that HDL lost its anti-diabetic function when the F2 mice developed severe dyslipidemia on the Western diet. Indeed, a high fat diet and subsequent dyslipidemia induce oxidative stress and inflammation [ 48 , 49 ], which can alter the structure and function of HDL, making it dysfunctional [ 50 ].…”

A Potential Interplay between HDLs and Adiponectin in Promoting Endothelial Dysfunction in Obesity

“…HDLs are a heterogeneous and complex class of lipoproteins with density ranging from 1.063–1.210 g/mL, considerable differences in size, shape, composition and function, produced mainly by the liver and, to a lesser extent, by the small intestine. In human plasma, the large, less dense (1.063–1.125 g/mL) lipid-enriched HDL2 and the small, dense (1.125–1.210 g/mL) protein-enriched HDL3 represent the two major sub-classes of HDLs [ 57 ]. HDLs contain several apolipoproteins (Apos) of which ApoA-I is quantitatively the most relevant and characterizes this lipoprotein class.…”

“…HDLs contain several apolipoproteins (Apos) of which ApoA-I is quantitatively the most relevant and characterizes this lipoprotein class. Other Apos are ApoA-II, ApoA-IV, ApoC-I, ApoC-II, ApoC-III, ApoC-IV, ApoD, ApoE, ApoF, ApoH, ApoJ, ApoL-I and ApoM [ 57 ]. In addition, several enzymes circulate in the bloodstream associated with HDLs, including enzymes involved in lipoprotein remodeling (lecithin-cholesterol acyltransferase, LCAT, cholesterol ester transfer protein, cholesteryl ester transfer protein CETP, and phospholipid transfer protein, PLTP), paraoxonase-1 (PON-1) and lipopolysaccharide (LPS)-binding protein (LBP) [ 58 ].…”

“…As shown in Figure 1 a, upon the binding of HDLs to their receptors as well as to S1P receptors, various kinases, including Src, AMPK, p38 MAPK, PI3K and Akt, are activated [ 60 , 61 ]. As a result, HDLs enhance endothelial barrier-function and exert anti-inflammatory, anti-apoptotic and anti-adhesive properties [ 57 , 62 , 63 , 64 ]. In addition, HDLs reduce the cellular production of superoxide, an inactivator of the vasodilator NO, by decreasing the activity of endothelial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [ 65 ], thus preventing ED.…”

“…Another well-known function of HDLs is their role as anti-inflammatory regulators exerted through interactions with both the vascular endothelium and circulating inflammatory cells [ 69 ]. As mentioned above, HDLs reduce the expression of endothelial adhesion molecules in response to inflammatory mediators and the migration of monocytes into the vascular wall, simultaneously exploiting their antioxidant activities [ 57 ]. HDLs prevent the induction of endothelial 32-kDa putative cysteine protease (CPP32)-like protease, resulting in a decrease in the activity of TNF-α, and, consequently, reduce the apoptotic rate of these cells [ 70 ].…”