High-Density Lipoprotein Modifications: A Pathological Consequence or Cause of Disease Progression?

Abstract

High-density lipoprotein (HDL) is well-known for its cardioprotective effects, as it possesses anti-inflammatory, anti-oxidative, anti-thrombotic, and cytoprotective properties. Traditionally, studies and therapeutic approaches have focused on raising HDL cholesterol levels. Recently, it became evident that, not HDL cholesterol, but HDL composition and functionality, is probably a more fruitful target. In disorders, such as chronic kidney disease or cardiovascular diseases, it has been observed that HDL is modified and becomes dysfunctional. There are different modification that can occur, such as serum amyloid, an enrichment and oxidation, carbamylation, and glycation of key proteins. Additionally, the composition of HDL can be affected by changes to enzymes such as cholesterol ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and phospholipid transfer protein (PLTP) or by modification to other important components. This review will highlight some main modifications to HDL and discuss whether these modifications are purely a consequential result of pathology or are actually involved in the pathology itself and have a causal role. Therefore, HDL composition may present a molecular target for the amelioration of certain diseases, but more information is needed to determine to what extent HDL modifications play a causal role in disease development.

Keywords: HDL modifications; dysfunctional HDL; high-density lipoproteins; inflammation.

Figure 1

Simplified overview of HDL synthesis and metabolism. The liver and intestines produce apoA-I which becomes discoidal nascent HDL after interaction with ATP-binding cassette transporter A1 (ABCA1). Lipidation of discoidal nascent HDL with unesterified cholesterol and phospholipids via ABCA1, ABCG1, and scavenger receptor B type 1 (SR-B1) and cholesterol esterification via lecithin-cholesterol acyltransferase (LCAT) produces spherical HDL₃ and further lipidation results in HDL₂ (only representative cross sections shown). Cholesterol is transported to the liver directly from HDL₂ via a not yet identified HDL receptor (HDLR) or through binding with SR-B1 (to be excreted by kidneys) or indirectly via interaction of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and intermediate-density lipoprotein (IDL) with LDL receptor (LDLR) following uptake of cholesterol and triglycerides from HDL₂, which is facilitated by cholesterol ester transfer protein (CETP). Recycling of HDL₂ occurs by the remodeling into lipid-poor and denser HDL₃ catalyzed by endothelial lipase (EL), hepatic lipase (HL), and phospholipid transfer protein (PLTP), which can once again undergo further lipidation. Solid arrows refer to specific steps in HDL metabolism and maturation, while dotted arrows reflect the transfer of triglycerides and unesterified cholesterol from peripheral cells to specific particles by interaction with displayed receptors.

Figure 2

Simplified diagram of serum amyloid A (SAA) modified HDL particle resulting in a dysfunctional HDL. SAA can displace apoA-I, PON1 and PAF-AH.

Figure 3

Simplified diagram of effects of inflammation on HDL bound apoM and sphingosine 1-phosphate (S1P) resulting in dysfunctional HDL.

Figure 4

Simplified diagram of effects of inflammation on HDL bound paraoxonase 1 (PON1) resulting in dysfunctional HDL.

Figure 5

Simplified diagram of myeloperoxidase (MPO) modified dysfunctional HDL.