**2. Physicochemical characteristics and metabolic process of LDL**

LDL is a spherical particle, core lipids of LDL particle are composed of cholesterol ester (CE) and triglyceride (TG), an outer monolayer is composed of free cholesterol (FC) and phospholipid (PL) including phosphatidylcholine (PC), and one molecule of apolipoprotein B100 surrounds the LDL particle [1]. Apolipoprotein

B-100 (apoB-100) is composed of the amphoteric α-helical domain and β-sheet domain alternately (NH2-βα1-β1-α2-β2-α3-coOH), in which β-sheet structure accounts for 40%, which is related to the stability of LDL particles, and α-helix accounts for 25%, which is related to the amphiphilicity of LDL particles and the potential of self-repair [2].

LDL is the plasma metabolite of very low-density lipoprotein (VLDL). Plasma lipoprotein lipase or liver lipase catalyzes the hydrolysis of triglyceride (TG) in VLDL particles. At the same time, under the action of cholesterol ester transfer proteins (CETPs), cholesterol ester (CE) of HDL is transferred to VLDL, and phospholipids, apolipoprotein C (ApoC), and cholesterol are transferred to high-density lipoprotein (HDL) on the surface of VLDL. This process continues. In VLDL, TG decreases continuously, CE increases gradually, particles become smaller, and density increases gradually. First intermediate density lipoprotein (IDL) is formed, and then LDL is formed [3]. According to the formation process of LDL, it is easy to see that LDL is not a kind of particle but a class of particles with different sizes, densities, chemical composition, or different charges. In recent years, LDL particles have been divided into two phenotypes: type A (large and light LDL), LDL particle diameter ≥25.5 nm, and type B (small and dense LDL, sd-LDL), LDL particle diameter <25.5 nm. Compared with type A LDL, sd-LDL has a stronger ability to cause atherosclerosis and has been identified for a long time as a new risk factor of cardiovascular disease by the American Cholesterol Education Program and Adult Treatment Program III (NCEPIII) [4].

Natural LDL (nLDL) is in charge of the transport of endogenous cholesterol, and its metabolic process is the transport process of endogenous cholesterol. Among them, two-third were metabolized through the LDL receptor pathway [5]. LDL receptor (LDLR) is widely distributed in the whole body, especially on the cell membrane surface of the liver, adrenocortical, ovarian, testicular, and arterial wall, and specifically binds to ApoB100 on the surface of LDL. Internalization causes the membrane at the junction to sink in for endocytosis. Under the action of the proton pump (H+ -ATPase), the pH of endocytotic vesicle contents decreased, and LDL is separated from the receptor and fused with the lysosome. ApoB100 is decomposed into amino acids by a lysosomal proteolytic enzyme, and CE is hydrolyzed into free cholesterol and fatty acids by cholesterol esterase for cell utilization.

The remaining one-third is cleared by the mononuclear macrophage pathway. As a major member of innate immunity, macrophages are endowed with an advanced arsenal of sensors, composed of various pattern-recognition receptors (PRR). It is able to identify and bind foreign substances or altered substances to inactivate and degrade them. Therefore, the monocyte–macrophage clearance pathway is mainly aimed at LDL, which has changed its structure for a variety of reasons. It can also be called modified LDL (mLDL). mLDL specifically binds to the scavenger receptors (SRs) on the surface of macrophages and is subsequently removed. The half-life of plasma LDL in normal people is 2–4 days.

The cells prepare their cholesterol needs via two pathways: an exogenous pathway mediated with the LDLR and an endogenous pathway activated with the substrates of mevalonate and HMG-CoA reductase [6]. When the intracellular cholesterol level is too high, sterol regulatory element-binding protein (SREBP), a nuclear transcription factor, is activated, which inhibits the expression of LDL receptor gene from the transcription level, inhibits the synthesis of the receptor protein, and reduces the further uptake of LDL by the cell [7]. It is suggested that the simple increase of the nLDL-C level cannot fully explain the occurrence of atherosclerotic disease. More significantly, contrary to LDLR, SR expression is not inhibited by elevated intracellular cholesterol levels [1]. Then, when the number of modified LDL absorbed by macrophages through SRs far exceeds their scavenging

**161**

**of apoB-100**

*Low-Density Lipoprotein: Biochemical and Metabolic Characteristics and Its Pathogenic…*

**3. LDL modification: endowing LDL with special biological activity**

**3.1 Changes in lipid composition of LDL particles and primary structure** 

At present, more research is placed on the effects of oxidation and glycosylation

LDL oxidation: when circulating LDL is out of extremely high levels, oxidized LDL (ox-LDL) is rarely found in circulation due to the presence of plasma antioxidants and vitamin C. In this case, the oxidation of LDL occurs mainly in the arterial wall. Vascular wall cells (endothelial cells, smooth muscle cells, and macrophages), stimulated by the attack factors, produce and release a large number of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Free radicals rapidly oxidize the polyunsaturated fatty acids (PUFAs) on the surface of LDL into fatty acid fragments [10, 11]. This modification is produced in the surface of the LDL particles, so the physical and chemical properties of LDL change little. We call this LDL the "minimum modified LDL," which retains the affinity for the LDL receptor. Then the "minimum modified LDL" activates the endothelial anti-apoptosis signaling pathway, induces endothelial cells to express tissue factors and chemokines, promotes the aggregation of inflammatory cells, triggers an inflammatory reaction, generates a large number of free radicals, and leads to the continuous oxidation of LDL. Continuous oxidation further converts fatty acid fragments into aldehydes**,** and aldehydes interact with the lysine residues of apoB-100 to form new antigenic determinants, inducing the formation of autoantibodies [12, 13]. After complete oxidation, ox-LDL completely loses its affinity to LDLR and binds specifically to the

With an extremely high level of circulating LDL, the antioxidants in the body are insufficient to maintain the antioxidant protection of nLDL. And nLDL oxidizes rapidly even without strong attack factors. Meanwhile, high levels of LDL, in turn, promote the binding of NO with hydrogen peroxide to produce peroxynitrite (ONOO-), which is a strong oxidant and constantly attacks endothelial cells, result-

LDL glycosylation: LDL glycosylation is a nonenzymatic reaction, and the reaction rate depends on the level of glucose and the duration of exposure [17]. The 67th amino acid region of the N-terminus of apoB-100 is the main site of glycosylation and also the attachment site of LDLR. Glycosylation at this site reduces the affinity of LDL to LDLR, promotes the uptake of LDL by SRs on the surface of macrophages, and induces the formation of foam cells. Glycosylation of LDL enhances the susceptibility to further oxidation of LDL. In addition, the glycosylation process is accompanied by the production of free radicals, which often result in the simultaneous existence of LDL glycosylation and LDL oxidation [18]. This is among the

causes of peripheral vascular disease in patients with advanced diabetes.

**3.2 Changes in lipid content of LDL particles and secondary structure** 

The conformation of apoB-100 on the surface of LDL is more dependent on the physical and chemical state of the lipid core, which is linked to the shape and

capacity, significant cholesterol accumulation will occur in macrophages, and then macrophages will be transformed into foam cells, which is a key link in the occur-

*DOI: http://dx.doi.org/10.5772/intechopen.86872*

rence of atherosclerosis [8, 9].

scavenger receptors (SRs) [14].

ing in endothelial dysfunction [15, 16].

**of apoB-100**

on LDL.

capacity, significant cholesterol accumulation will occur in macrophages, and then macrophages will be transformed into foam cells, which is a key link in the occurrence of atherosclerosis [8, 9].
