**5. Dysfunctional HDL in systemic inflammation**

The potent atheroprotective effects of HDL originate from its unique composition and structure. If the composition or structure of HDL is altered in the setting of systemic inflammation (e.g., CVD and diabetes mellitus), it may lose its protective effects and even acquire deleterious functions, which is called dysfunctional HDL [106, 107]. Moreover, changes of HDL functions in systemic inflammation can also be the results of chemical modifications of HDL components without changing its composition. The most common modifications of HDL are oxidation and glycation of its proteins or lipids [9, 108]. Therefore, understanding the features of dysfunctional HDL might lead to a new diagnostic and therapeutic approach to CVD.

### **5.1 Dysfunctional HDL in CVD**

In the early phase of acute myocardial infarction, the pro-inflammatory HDL particles display remarkable alterations, including increased levels of lysophosphatidylcholine (LysoPC), phosphatidic acid (PA), ceruloplasmin, and serum amyloid A (SAA); decreased amounts of apoA-I, PON1, and platelet-activating factor acetylhydrolase (PAF-AH); and reduced abilities of cholesterol efflux and anti-oxidative activity, which are implicated in the impaired functions of HDL [109, 110].

Myeloperoxidase (MPO) is released to plasma from monocytes and neutrophils in CVD, which uses hydrogen peroxide to generate hypochlorous acid (HClO) and subsequently causes oxidative modifications of lipids and proteins of lipoproteins, rendering HDL dysfunctions [111, 112]. Some studies found that MPO-dependent oxidation of HDL reduces the binding affinity of HDL to receptors and impairs its ability to stimulate cholesterol efflux from foam cells [113, 114]. Meanwhile, oxidized HDL (ox-HDL) can induce ROS production and upregulate the expression of pro-inflammatory and pro-thrombotic genes, such as TNF-alpha, matrix metalloproteinase-2/-9 (MMP-2/-9), COX-2, and plasminogen activator inhibitor-1 (PAI-1), which elevates CVD risk [115–117]. In addition, ox-HDL is dysfunctional in inducing NO production and promoting endothelial repair *in vitro* and reendothelialization of injured carotid arteries *in vivo* [118, 119]. And ox-HDL also promotes VSMC proliferation and migration by triggering intercellular ROS production [120]. Furthermore, ox-HDL has an elevated capability to induce the proliferation, migration, and invasion of breast cancer cells, thereby promoting the metastasis of breast cancer [103, 121].

#### **5.2 Abnormal HDL in diabetes mellitus**

HDL could be deficient in T2DM conditions, because of enrichment of TG, depletion of CE, and glycation of apoA-I and HDL-associated enzymes. These changes impair the structure and function of HDL, reduce receptor-mediated cholesterol efflux, and increase CVD risk [122, 123]. Glycation of HDL *in vitro* reduces its capacity to mediate cholesterol efflux from THP-1 macrophages, and incubation

**21**

*High-Density Lipoprotein: From Biological Functions to Clinical Perspectives*

with glycation inhibitors (metformin and aminoguanidine) restores HDL-mediated cholesterol efflux [124, 125]. HDL from diabetic subjects reduces the abilities of anti-oxidation and anti-apoptosis as well as the capacities to mediate cholesterol efflux from THP-1 macrophages, which result from depleting HDL-associated apoA-I level and PON1 activity and elevating SAA concentration [126–128]. Both glycated HDL *in vitro* and diabetic HDL lose their protective effects on inhibition of cytokine release against LPS in macrophages [129]. Moreover, diabetic HDL is less effective to stimulate NO production, to promote proliferation and migration in endothelial cells by downregulating SR-BI, and to improve endothelium-dependent vasodilation and endothelial repairment [130, 131]. In addition, HDL from diabetic patients leads to abnormal actions on breast cancer cell adhesion to endothelial cells and extracellular matrix, thereby promoting the metastasis of breast cancer [132]. HDL from T2DM patients carries a higher level of S1P, which could be partly responsible for the abnormal functions of diabetic HDL [133]. CETP activity is elevated in diabetic patients compared to healthy subjects, resulting in changed HDL remodeling and accelerated HDL clearance [134]. ApoA-I is glycated in T2DM patients *in vivo* and by glucose or methylglyoxal *in vitro*, and such glycation may impair its anti-inflammatory effects in endothelial cells [135, 136]. Some specific lysine (K) residues of apoA-I (K12, K23, K40, K96, K106, K107, and K238) are susceptible to be glycated either *in vitro* or *in vivo*, which alter the conformation of apoA-I and consequently impair the anti-inflammatory effects of apoA-I in diabetic conditions [137].

Plasma levels of ox-HDL in T2DM patients were reported to be higher than those in healthy individuals [138]. It was found that ox-HDL is independently and positively correlated with fasting glucose levels, suggesting that high glucose levels may also contribute to HDL oxidation [139]. Glycated HDL is more susceptible to oxidation *in vitro* as shown by an increase in lipid peroxidation products and thiobarbituric acid-reactive substances (TBARS) following incubation of HDL with glucose.

HDL comprises a heterogeneous group of discoid and spherical particles (7–12 nm in diameter) that differ in density, size, and electrophoretic mobility [30]. As whether plasma HDL-C levels could really reflect the whole HDL compositions and whether HDL-C is still a good predictor for CVD are questioned; quantitative measurements of HDL particles (HDL-P) might be more valuable and meaningful than HDL-C [140]. In addition, HDL is a complex carrier for many kinds of proteins, lipids, and other biochemical materials in plasma as mentioned above, which might make it to be the natural endogenous nanoparticles that deliver cargoes

Distinct content in proteins and lipids results in various HDL subclasses, each characterized by differences in shape, density, size, and charge. Broadly, HDL can be distinguished into two subfractions by density: HDL2 and HDL3. HDL2 is larger, less dense, and strongly associated with apoA-I, which carries the majority of cholesterol reflected in HDL-C measurements. Unlike HDL2, HDL3 carries proteins that prevent oxidative stress and receive cholesterol from RCT through ABCA1. HDL3 cholesterol is well approximated by the sum of small and medium HDL-P concentration, whereas HDL2 cholesterol correlates strongly with large HDL-P concentration. By the action of LCAT, small HDL3 is progressively transformed to CE-enriched HDL2. CETP mediates the hetero-transfer of TG and CE between

*DOI: http://dx.doi.org/10.5772/intechopen.91136*

**6. HDL particles (HDL-P)**

targeted to recipient cells.

**6.1 HDL subclasses**

#### *High-Density Lipoprotein: From Biological Functions to Clinical Perspectives DOI: http://dx.doi.org/10.5772/intechopen.91136*

*Apolipoproteins, Triglycerides and Cholesterol*

**5.1 Dysfunctional HDL in CVD**

smoking, obesity, and diabetes mellitus) and a shared biology [99]. Low HDL-C levels might be a prognostic factor for biliary tract cancer, prostate cancer, colon cancer, breast cancer, and gastric cancer [100, 101]. *In vitro* studies also demonstrated that native HDL could inhibit the migration and invasion of breast cancer cells [102, 103]. In addition, HDL could repress the adhesion of breast cancer cells to endothelial cells that mitigate the metastasis of breast cancer and reduce cancer

The potent atheroprotective effects of HDL originate from its unique composition and structure. If the composition or structure of HDL is altered in the setting of systemic inflammation (e.g., CVD and diabetes mellitus), it may lose its protective effects and even acquire deleterious functions, which is called dysfunctional HDL [106, 107]. Moreover, changes of HDL functions in systemic inflammation can also be the results of chemical modifications of HDL components without changing its composition. The most common modifications of HDL are oxidation and glycation of its proteins or lipids [9, 108]. Therefore, understanding the features of dysfunctional HDL might lead to a new diagnostic and therapeutic approach to CVD.

In the early phase of acute myocardial infarction, the pro-inflammatory HDL particles display remarkable alterations, including increased levels of lysophosphatidylcholine (LysoPC), phosphatidic acid (PA), ceruloplasmin, and serum amyloid A (SAA); decreased amounts of apoA-I, PON1, and platelet-activating factor acetylhydrolase (PAF-AH); and reduced abilities of cholesterol efflux and anti-oxidative

Myeloperoxidase (MPO) is released to plasma from monocytes and neutrophils in CVD, which uses hydrogen peroxide to generate hypochlorous acid (HClO) and subsequently causes oxidative modifications of lipids and proteins of lipoproteins, rendering HDL dysfunctions [111, 112]. Some studies found that MPO-dependent oxidation of HDL reduces the binding affinity of HDL to receptors and impairs its ability to stimulate cholesterol efflux from foam cells [113, 114]. Meanwhile, oxidized HDL (ox-HDL) can induce ROS production and upregulate the expression of pro-inflammatory and pro-thrombotic genes, such as TNF-alpha, matrix metalloproteinase-2/-9 (MMP-2/-9), COX-2, and plasminogen activator inhibitor-1 (PAI-1), which elevates CVD risk [115–117]. In addition, ox-HDL is dysfunctional in inducing NO production and promoting endothelial repair *in vitro* and reendothelialization of injured carotid arteries *in vivo* [118, 119]. And ox-HDL also promotes VSMC proliferation and migration by triggering intercellular ROS production [120]. Furthermore, ox-HDL has an elevated capability to induce the proliferation, migration, and invasion of breast cancer cells, thereby promoting the metastasis of

HDL could be deficient in T2DM conditions, because of enrichment of TG, depletion of CE, and glycation of apoA-I and HDL-associated enzymes. These changes impair the structure and function of HDL, reduce receptor-mediated cholesterol efflux, and increase CVD risk [122, 123]. Glycation of HDL *in vitro* reduces its capacity to mediate cholesterol efflux from THP-1 macrophages, and incubation

activity, which are implicated in the impaired functions of HDL [109, 110].

growth through inhibiting tumor angiogenesis [104, 105].

**5. Dysfunctional HDL in systemic inflammation**

**20**

breast cancer [103, 121].

**5.2 Abnormal HDL in diabetes mellitus**

with glycation inhibitors (metformin and aminoguanidine) restores HDL-mediated cholesterol efflux [124, 125]. HDL from diabetic subjects reduces the abilities of anti-oxidation and anti-apoptosis as well as the capacities to mediate cholesterol efflux from THP-1 macrophages, which result from depleting HDL-associated apoA-I level and PON1 activity and elevating SAA concentration [126–128]. Both glycated HDL *in vitro* and diabetic HDL lose their protective effects on inhibition of cytokine release against LPS in macrophages [129]. Moreover, diabetic HDL is less effective to stimulate NO production, to promote proliferation and migration in endothelial cells by downregulating SR-BI, and to improve endothelium-dependent vasodilation and endothelial repairment [130, 131]. In addition, HDL from diabetic patients leads to abnormal actions on breast cancer cell adhesion to endothelial cells and extracellular matrix, thereby promoting the metastasis of breast cancer [132]. HDL from T2DM patients carries a higher level of S1P, which could be partly responsible for the abnormal functions of diabetic HDL [133]. CETP activity is elevated in diabetic patients compared to healthy subjects, resulting in changed HDL remodeling and accelerated HDL clearance [134]. ApoA-I is glycated in T2DM patients *in vivo* and by glucose or methylglyoxal *in vitro*, and such glycation may impair its anti-inflammatory effects in endothelial cells [135, 136]. Some specific lysine (K) residues of apoA-I (K12, K23, K40, K96, K106, K107, and K238) are susceptible to be glycated either *in vitro* or *in vivo*, which alter the conformation of apoA-I and consequently impair the anti-inflammatory effects of apoA-I in diabetic conditions [137].

Plasma levels of ox-HDL in T2DM patients were reported to be higher than those in healthy individuals [138]. It was found that ox-HDL is independently and positively correlated with fasting glucose levels, suggesting that high glucose levels may also contribute to HDL oxidation [139]. Glycated HDL is more susceptible to oxidation *in vitro* as shown by an increase in lipid peroxidation products and thiobarbituric acid-reactive substances (TBARS) following incubation of HDL with glucose.
