High-Density Lipoprotein Alterations in Type 2 Diabetes and Obesity

Abstract

Alterations affecting high-density lipoproteins (HDLs) are one of the various abnormalities observed in dyslipidemia in type 2 diabetes mellitus (T2DM) and obesity. Kinetic studies have demonstrated that the catabolism of HDL particles is accelerated. Both the size and the lipidome and proteome of HDL particles are significantly modified, which likely contributes to some of the functional defects of HDLs. Studies on cholesterol efflux capacity have yielded heterogeneous results, ranging from a defect to an improvement. Several studies indicate that HDLs are less able to inhibit the nuclear factor kappa-B (NF-κB) proinflammatory pathway, and subsequently, the adhesion of monocytes on endothelium and their recruitment into the subendothelial space. In addition, the antioxidative function of HDL particles is diminished, thus facilitating the deleterious effects of oxidized low-density lipoproteins on vasculature. Lastly, the HDL-induced activation of endothelial nitric oxide synthase is less effective in T2DM and metabolic syndrome, contributing to several HDL functional defects, such as an impaired capacity to promote vasodilatation and endothelium repair, and difficulty counteracting the production of reactive oxygen species and inflammation.

Keywords: cholesterol efflux; endothelium; glycoxidation; high-density lipoprotein; metabolic syndrome; obesity; type 2 diabetes.

Figure 1

Main changes in the size and composition of HDLs in T2DM and MetS. ↗ and ↘ mean increase and decrease, respectively. AGEs, advanced glycation end-products; CE, cholesteryl esters; CETP, cholesteryl ester transfer protein; MDA, malondialdehyde; PCs, phosphatidylcholines; PEs, phosphatidylethanolamines; PON, paraoxonase; SAA, serum amyloid A; TG, triglycerides.

Figure 2

Impaired atheroprotective functions of carbamylated HDLs. ↗ and ↘ mean increase and decrease, respectively. Green arrows represent the functions of healthy HDLs. (1) Carbamylated HDLs partially lose their ability to remove cholesterol from macrophages, and (2) to inhibit monocyte adhesion and recruitment into the subendothelial space. (3) Carbamylated HDLs are less able to protect LDLs from oxidation, likely due to reduced lecithin-cholesterol acyltransferase (LCAT) and paraoxonase-1 (PON1) activity. (4) Lastly, carbamylated HDLs have an impaired capacity to facilitate endothelial repair.

Figure 3

Anti-inflammatory functions of HDLs in T2DM and MetS. ↑ means increase. The inflammatory NF-κB pathway is triggered by several mediators, including TNF-α, advanced glycation end-products (AGEs), modified LDLs, reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress. This leads to an increased gene expression of adhesion molecules, proinflammatory cytokines, and NADPH oxidase (NOX2). Green arrows represent the functions of healthy HDLs. (1) The binding of HDLs to receptors is modified by conformational changes in HDL particles in insulin resistant conditions. The depletion in S1P of MetS HDLs likely decreases the binding to S1P receptors (S1PR). (2) HDL-mediated protection of LDLs against oxidation is affected, (3) in particular due to the loss of capacity of HDLs to dampen ROS production. This promotes the NF-κB activation triggered by the recognition of oxidized LDLs by scavenger receptors in vasculature, particularly by LOX-1 (i.e., SR-E1) and SR-A1. (4) The activation of endothelial NO synthase by HDLs is reduced (see 4.3) and subsequently inhibits nitrosylation of NF-κB. (5) Ultimately, HDLs are less able to inhibit the translocation of NF-κB into the nucleus, and, (6) afterwards, the gene expression of adhesion molecules and proinflammatory cytokines. (7) This facilitates the recruitment of immune cells into the subendothelial space.

Figure 4

NO-mediated HDL functions in T2DM and MetS. ↑ and ↘ mean increase and decrease, respectively. Green arrows represent the functions of healthy HDLs. (1) HDLs from T2DM and non-diabetic MetS individuals are less able to induce Akt-dependent eNOS phosphorylation at Ser1177. (2) HDL-mediated protection of LDLs against oxidation is affected, thus facilitating eNOS inhibition after the binding of modified LDLs to LOX-1. (3) Oxidized HDLs are also able to bind to LOX-1 receptor, leading to PKCβII activation and subsequently to eNOS inhibition. (4) The loss of capacity of HDLs to dampen ROS production promotes eNOS uncoupling. (5) Ultimately, HDL-mediated NO production is reduced, (6) affecting the relaxation of vascular smooth muscle cells and (7) endothelium repair. (8) Reduced NO synthesis diminishes the inhibition of nitrosylation of NF-κB, as well as NOX2-mediated ROS production and the recruitment of immune cells into the subendothelial space.