**4. HDL functions beyond RCT**

HDL exerts diverse biological functions besides removing cholesterol from peripheral cells through RCT, which have attracted considerable attentions.

### **4.1 Endothelial cell protections of HDL**

Endothelial cells play fundamental roles in regulating vascular functions [72, 73]. Many risk factors for atherosclerosis (e.g., hypercholesterolemia, hypertension, and hyperglycemia) induce the inflammation and apoptosis in endothelial cells and initiate the pathogenesis of atherosclerosis [74]. Therefore, improving endothelial dysfunction is a potential target for preventing and treating CVD. HDL could inhibit cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and ICAM-1 in human umbilical vein endothelial cells (HUVECs) and reduce the adhesion of monocytes to endothelial cells [75]. Moreover, HDL induces endothelial repair by enhancing eNOS activity and increasing NO production through the SR-BI and ABCG1 pathways [76, 77]. HDL also improves vascular

**19**

**4.5 HDL and cancer**

[83].

**4.3 HDL against inflammation**

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

**4.2 HDL functions on vascular smooth muscle cells (VSMCs)**

health by reducing apoptosis and promotes proliferation and migration in endothelial cells, which are crucial for neovascularization after vascular injuries [78].

Many stress factors could induce VSMCs shifting from a contractile phenotype to a synthetic phenotype, and consequently the activated VSMCs proliferate and migrate from the medial layer of vessels into the intima which results in neointimal hyperplasia and artery stenosis [79, 80]. HDL counterbalances the pro-inflammatory effects of ox-LDL by inhibiting intracellular reactive oxygen species (ROS) release and subsequent nuclear factor kappa-B (NF-κB) activation in VSMCs [81]. HDL also downregulates the production of fibroblast growth factor (FGF) and represses the proliferation of VSMCs triggered by ox-LDL [82]. HDL suppresses the expression of chemokines (CCL2, CCL5, CX3CL1, CCR2, and CX3CR1) and the proliferation of VSMCs induced by TNF-alpha via the SR-BI pathway [7]. In addition, HDL-associated alpha-antitrypsin (AAT) inhibits extracellular matrix degradation, cell detachment, and apoptosis triggered by elastase in human VSMCs

HDL plays an important role against inflammatory responses [84, 85]. HDL is able to bind and neutralize LPS as well as to facilitate LPS release from the surface of macrophages, which inhibits macrophage activation and cytokine release [85–87]. HDLbound LPS does not interact with the cellular membrane receptors in macrophages, thereby decreasing the uptake of LPS by macrophages. And apoA-I is identified as the LPS-binding molecule in HDL [88]. In rat models of LPS-mediated sepsis, infusion of rHDL significantly reduces cytokine release, organ injuries, and animal mortality [89]. In addition, elevation of plasma HDL-C levels in transgenic mice by overexpressing apoA-I protects against septic shock and death caused by LPS and severe bacterial infection [90]. Similarly, low levels of HDL-C increase the mortality in patients with sepsis/septic shock [91]. Systemic administration of rHDL blunts the deleterious effects of LPS caused by small doses of intravenous LPS injection in human volunteers, such as attenuating cytokine release, correcting procoagulant state, and downregulating CD14 expression [92, 93]. Furthermore, HDL was shown to suppress cytokine and chemokine production, downregulate co-stimulatory molecules, and inhibit antigen

presentation in macrophages and monocyte-derived dendritic cells [94].

HDL may favorably regulate glucose metabolism. HDL promotes glycogen synthesis in skeletal muscle myocytes via SR-BI and stimulates glucose uptake by adipocytes [95]. HDL and apoA-I stimulate glucose uptake by skeletal muscle myocytes via increasing adenosine monophosphate-activated protein kinase (AMPK) activity [96]. HDL also enhances insulin secretion by pancreatic beta cells, which requires ABCA1-mediated cholesterol efflux as well as SR-BI expression [97]. In patients with type 2 diabetes mellitus (T2DM), intravenously injecting rHDL increases plasma insulin levels and decreases glucose concentrations *in vivo* [98].

Epidemiological studies showed that CVD and cancer possess various similarities and possible interactions, including a number of common risk factors (e.g.,

**4.4 Regulation of glucose metabolism by HDL**

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

health by reducing apoptosis and promotes proliferation and migration in endothelial cells, which are crucial for neovascularization after vascular injuries [78].
