Normal protein and lipid components of HDL.
Lipoproteins are complexes of lipids and proteins that carry water‐insoluble cholesterol in the bloodstream. While cholesterol is required for normal cell function, hypercholesterolemia contributes to the development of cardiovascular disease (CVD). Increased low‐density lipoprotein (LDL) is a major risk factor for CVD. Reduced high‐density lipoprotein (HDL) levels are inversely related to CVD risk, suggesting a protective role for HDL. Several diseases, including atherosclerosis, diabetes, chronic kidney disease and rheumatoid arthritis, have been identified where HDL levels are decreased or function is compromised. HDLs are spherical particles with a hydrophobic core of cholesteryl esters surrounded by a monolayer of phospholipids, proteins and unesterified cholesterol. Apolipoprotein (apo) A‐I, the major protein component of HDL, plays an important role in the assembly and function of HDL. One of the major functions of HDL is to mediate cellular cholesterol efflux and the transfer of cholesterol from extrahepatic tissues to the liver for excretion into the bile. In addition to regulating cholesterol metabolism, HDL also exhibits antioxidative, antithrombotic and anti‐inflammatory properties. Under certain conditions, however, HDL may undergo biochemical modification resulting in the formation of a particle with pro‐inflammatory properties. This review will focus on the variable properties of HDL under normal physiological conditions and in the context of inflammation.
- lipid composition
- protein composition
- macrophage mitochondria
Hypercholesterolemia is an important determinant of cardiovascular disease (CVD), the leading cause of death globally . Cholesterol, among other lipids, is carried in the bloodstream from the liver to different parts of the body by lipoproteins, complex particles composed of lipids and proteins. There are four major lipoproteins that can be classified on the basis of their density: chylomicrons, very low‐density lipoprotein (VLDL), low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) . Chylomicrons, VLDL and LDL are larger particles with densities ranging from 0.95 to 1.063 g/ml. HDL is a mixture of spherical particles ranging in size from 7 to 12 nm in diameter and 1.063–1.21 g/ml in density. Epidemiological studies have established an inverse relationship between HDL cholesterol and CVD risk [3, 4]. Thus, a reduction in plasma HDL levels represents an important risk factor for CVD. Results of clinical trials demonstrate that lowering LDL levels reduces CVD risk [5, 6]. Evidence supporting a role for elevated HDL in reducing CVD risk, however, is still forthcoming. Clinical trials have shown that torcetrapib, dalcetrapib and extended‐release niacin significantly increase circulating HDL levels; however, this was not associated with improved outcomes [7–9]. On the other hand, raising plasma HDL by infusion or overexpression of apoA‐I in murine models was shown to reduce atherogenic lesion progression . One hypothesis to explain this disparity proposes that the “quality” or functional status of HDL may be a better indicator of CVD risk than plasma levels of HDL per se . This review will focus on the structure‐function relationship of HDL and how it influences responses to the lipoprotein in the context of inflammation.
HDL particles have a neutral core of cholesteryl ester and triglycerides (TG) surrounded by a monolayer of phospholipids, free cholesterol (FC) and protein. ApoA‐I is the major protein associated with HDL particles and is synthesized in the liver and small intestine. Phospholipids and cholesterol are transferred to apoA‐I by a process mediated by the ATP‐binding cassette transporter type 1 (ABCA1) [12, 13] resulting in the formation of a lipid poor, dense particle called preβ‐HDL. This particle plays an important role in reverse cholesterol transport, a process by which cholesterol is removed from cells. Although these particles have been predominantly studied under in vitro conditions, little information is available regarding the presence or functional significance of preβ‐HDL in vivo . HDL isolated from plasma by sequential ultracentrifugation yields two major subpopulations: HDL2, a large, light, lipid‐rich particle (d1.063–1.125 g/ml), and HDL3, a smaller, denser protein‐rich particle (d1.125–1.21 g/ml). These two particles can be further subdivided into five distinct populations: HDL2b, HDL2a, HDL3a, HDL3b and HDL3c . These heterogeneous particles vary in their lipid and protein composition, forming particles of varying density, charge, and antigenicity. They also possess discrete functional properties.
2. HDL structural components
Sphingolipids are also well‐represented in HDL particles. Sphingomyelin (SM) accounts for 5–10% by weight of total HDL lipids . SM is converted to ceramide by sphingomyelinase . Ceramide constitutes 0.05% by weight of total HDL lipids. Ceraminidase converts ceramide to sphingosine. Finally, the enzyme sphingosine kinase converts sphingosine to sphingosine 1‐phosphate (S1P) . S1P, as well as ceramide‐1‐phosphate, are carried by HDL and are potent signaling molecules that regulate cell growth, survival and differentiation . S1P plays an important role in the suppression of inflammation . S1P binding to HDL requires its physical interaction with apo M [17, 18]. Sphingosylphosphorylcholine and lysosulfatide are additional, biologically active lysosphingolipids carried by HDL . The principal lipids associated with HDL particles are summarized in Table 1.
|Apolipoproteins (AI‐II, A‐V, C‐I‐IV, D, E, F, M, H, O)||Phospholipids:|
|CETP||PC, PE, PI, PG, PS, PA|
|SAA1, SAA2, SAA4||S1P|
|Vitamin D binding protein|
3. Functions of HDL
ApoA‐I is likely the major HDL protein species involved in the removal of LOOH moieties from LDL. The methionine (Met) residues 112 and 148 of apoA‐I can reduce LOOHs to inactive lipid hydroxides (LOH) . In addition, apoA‐I removes seeding LOOH molecules from LDL . In addition to apoA‐I, other apolipoprotein and enzyme components of HDL, such as, apo E, apo J, apo A‐II, apo L‐1, apo F, apo A‐IV, PON1/3, PLTP and PAF‐AH, play a role in its antioxidant function. Proteomic analyses from the Davidson laboratory  demonstrate that HDL3c contains all these proteins along with apo M, apo D, apo A‐II, SAA1,2 and 4 and apo C‐I and apo C‐II. This corroborates earlier studies showing that HDL3c has more potent antioxidant activity than other HDL subspecies [31, 32]. Thus, both lipid and protein components of HDL3c contribute to its antioxidant activity. Kontush et al.  have hypothesized that the protein components of HDL3c form a pocket which enables the transfer of LOOH from LDL which is further reduced by the concerted action of apolipoproteins and enzymes in this pocket .
In the presence of ox‐LDL and other oxidized lipids, the mitochondrion increases the formation of ROS, which can damage the mitochondria and other organelles causing cellular dysfunction and death. HDL, by virtue of its antioxidant properties, can decrease the cellular damage caused by oxidized lipids. The HDL protein PON1 hydrolyzes cholesterol esters and phospholipids in oxidized lipoproteins [52, 57, 58] thus inhibiting mitochondrial damage in the presence of oxidized lipids . Further, HDL‐associated apoA-I has been implicated in electron transport chain maintenance and repair . In apoA‐I null mice (apoA‐I-/-), an increase in coronary ischemia‐reperfusion injury is observed compared to wild‐type mice  and is associated with a decrease in the content of the mitochondrial protein Coenzyme Q (CoQ) in cardiomyocytes. CoQ normally supports oxidative phosphorylation by shuttling electrons from Complex II to Complex III. Exogenous administration of CoQ to apo‐A‐I-/- mice attenuated myocardial infarct size compared to the injury response in untreated mice. These data indicate the importance of HDL, and specifically, apoA‐I in preserving mitochondrial structure and function.
Potential mechanisms by which HDL preserves mitochondrial function include activation of the Reperfusion Injury Salvage Kinase (RISK) pathway and the Survivor Activating Factor Enhancement (SAFE) cascade. These are cell survival pathways which are known to prevent mitochondrial damage in models of ischemic pre‐ and postconditioning . Activation of STAT3 is an important component of the SAFE pathway and results in the downregulation of pro‐apoptotic factors Bax and Bad and upregulation of antiapoptotic factor Bcl‐2 and the antioxidants manganese superoxide dismutase and metallothionein [60, 61]. Further, STAT3 is transported to the mitochondrion by the GRIM‐19 chaperone where it inhibits the release of cytochrome c and reduces cell death [62–64]. In a rodent model of coronary artery occlusion, the administration of apoA‐I was shown to decrease infarct size and inhibit mitochondrial morphological changes seen in the heart . Further analyses showed that apoA‐I increased the phosphorylation of
The S1P component of HDL is also able to activate the RISK And SAFE pathways [51, 52, 65]. Interestingly, studies conducted in neonatal rat cardiomyocytes showed that S1P is critically required for the phosphorylation of STAT3. In contrast, STAT3 phosphorylation was absent in cells treated with HDL that was deficient in S1P . In addition, S1P stimulates the phosphorylation of the transcription factor, forkhead box O‐1 (FOXO‐1), which inhibits ROS formation and apoptosis in the phosphorylated form [66, 67]. These data suggest that HDL activates RISK and SAFE pathways and inhibits ROS, mitochondrial dysfunction and cell death.
Interestingly, S1P has also been shown to regulate mitochondrial Complex IV assembly and cellular respiration by interacting with mitochondrial prohibitin‐2 (PBH‐2) . PBH‐2 acts as a scaffolding protein for mitochondria and its interaction with S1P during ischemic pre‐conditioning of cardiomyocytes is essential for cardioprotection [68–70]. These data suggest that S1P can stabilize mitochondrial complexes and inhibit ROS formation, suggesting an alternate cardioprotective mechanism of S1P action.
Recent studies have suggested that other HDL‐associated apolipoproteins play a role in preserving mitochondrial structure and function. ApoJ is expressed ubiquitously and is present on small dense HDL3 particles [71–73]. It is considered to be an antioxidant due to the presence of disulfide bonds that inhibit ROS‐induced injury and preserve mitochondrial function . Further, apoJ has been implicated in activating
4. Inflammation‐induced alterations in HDL structure
Changes in HDL sub‐species and their function have been reported in several disease states, including atherosclerosis , rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) [81, 82], diabetes , hypertension  and psoriasis [85–87]. Inflammation/infection triggers an APR that causes a reduction in HDL quantity and alterations in both its lipid and protein composition. Van Lenten and colleagues  first reported that HDL loses its ability to inhibit LDL oxidation during the APR, demonstrating that inflammation affects the structure and function of HDL.
|Serum Amyloid A (SAA)||Apo A‐I||Triglycerides||Total lipid|
|Apo J||Apo A‐II||FC||Phospholipids|
|Apo E||Apo M||FFA||SM|
|Apo A‐IV||Hepatic lipase|
|Apo A‐V||Paraoxanase I|
The presence of apoM in HDL particles is thought to contribute to atheroprotection . LPS and inflammatory cytokines, however, attenuate apoM mRNA levels and protein expression in Hep3B cells . A decrease in serum apoM is also observed in patients with sepsis and HIV infections . Further, a reduction in apoM reduces the association of S1P with HDL resulting in degradation of anti‐inflammatory function .
The association of other apolipoproteins with HDL may impair the function of the lipoprotein. ApoO is incorporated by HDL, LDL and VLDL particles . Data suggest that apoO provides structural stability for mitochondria by stabilizing the inner mitochondrial membrane and cristae . Other data, however, show that overexpression of apoO degrades mitochondrial protein and increases cardiac dysfunction in hypercholesterolemic mice . In cardiomyocyte cultures, upregulation of apoO was associated with an increase in ROS and apoptosis compared to control cells that were apoO‐deficient . ApoC is an additional, exchangeable apolipoprotein associated with HDL and apoB‐containing lipoproteins. In isolated rat liver mitochondria, addition of the apoC‐III isoform was shown to inhibit mitochondrial oxygen consumption and attenuate ATP formation . Another study showed that enrichment of HDL with apoC‐I stimulates cytochrome c release, caspase 3 cleavage and cell death in human aortic smooth muscle cells . Finally, apoC‐I enrichment of HDL is associated with a reduction in HDL‐associated apoA‐I, suggesting that loss of apoA‐I and its cytoprotective effects is a component of apoC‐I‐mediated cell injury [107, 108]. Clearly, additional in vitro and in vivo studies are required to define the mechanistic role of specific apolipoprotein species in the development of inflammatory injury.
5. Functional consequences of acute phase HDL formation
Changes in HDL lipid and protein composition induced by the APR impair normal HDL function resulting in the formation of “dysfunctional” HDL.
HDL plays an important role in regulating atherogenesis
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