**Abstract**

Dyslipidemia refers to a broad spectrum of various genetic and acquired disorders that affect blood lipid levels and largely contribute to global cardiovascular disease burden. Consistent evidence from epidemiological and clinical studies, supports the key role of the circulating LDL-cholesterol and other apoB containing lipoproteins in atherogenesis. All ApoB-containing lipoproteins with size less than 70 nm can cross the endothelial barrier, particularly in the presence of endothelial dysfunction. Uptake and accumulation of apoB-containing lipoproteins in the arterial wall is a critical initiating event in the development of atherosclerosis. Statin treatment, targeting LDL cholesterol reduction, remains the cornerstone of dyslipidemia management. There are abundant data supporting the concept of 'the lower LDL-C, the better' in the primary and secondary cardiovascular disease prevention. This chapter provides an overview of the key insights into the lipid abnormalities associated with an increased risk of CV events particulary in the context of dyslipidemia management in everyday clinical practice. Understanding the important role that metabolic derangements play in the pathogenesis of atherosclerosis pave the way for stronger implementation of current guidelines for CVD risk assessment and prevention.

**Keywords:** atherosclerosis, dyslipidemia, cardiovascular disease, lipid-lowering therapies, lipoproteins

### **1. Introduction**

Cardiovascular disease (CVD) remains a major cause of global mortality and rising health care costs worldwide. CVD burden is predominantly attributable to modifiable behavioral and metabolic risk factors with dyslipidemia being one of them [1, 2]. Dyslipidemia is a term that encompasses a broad spectrum of various genetic and acquired disorders that affect blood lipid levels. This chapter provides an overview of the key insights into the lipid abnormalities associated with an increased risk of CV events particularly in the context of dyslipidemia management in everyday clinical practice. Understanding the important role that metabolic derangements play in the pathogenesis of atherosclerosis paves the way for stronger implementation of current guidelines for CVD risk assessment and prevention.

## **2. Lipids and lipoproteins**

Lipids are essential components of the human body, having several important biological functions such as storing energy, acting as structural components of cell membranes and participating in signaling pathways. The three main types of lipids are phospholipids, sterols, and triglycerides (also known as triacylglycerols) [3]. In view of the fact that the term "lipid" has been defined as any of a group of organic compounds that are insoluble in water but soluble in organic solvents, lipids comprise a broad range of molecules such as fatty acids, triglycerides (TG), phospholipids, sterols, sphingolipids and many others. However, from a clinical standpoint, given their role in the pathogenesis of CVD, the two major forms of circulating lipids in the body are TG and cholesterol. Although insoluble in plasma, these lipids can be transported throughout the bloodstream as lipoproteins when packaged with phospholipids and proteins known as apoproteins or apolipoproteins.

Lipoproteins are complex particles that have a central hydrophobic core composed of non-polar lipids, primarily cholesterol esters (CE) and TG and a hydrophilic surface consisting of polar lipids (phospholipids and free cholesterol) and apoproteins. The protein component provides structural integrity to the framework of the lipoproteins and being attached to the surface of particles, make them detectable for enzymes and receptors. Hence, apoproteins modulate enzyme activity (eg, apoprotein C-II activates lipoprotein lipase) and serve as ligands, specific recognition sites for cell surface receptors during cellular uptake (eg, apoprotein B-100 binds to the low-density lipoprotein receptor).

Lipoproteins are synthesized in both the liver and the intestines, playing a key role in the absorption and transport of dietary lipids by the small intestine, in the transport of lipids from the liver to peripheral tissues, and from peripheral tissues to the liver and intestine (a process known as reverse cholesterol transport). Within the circulation, lipoproteins go through constant change in composition and physical structure as the peripheral tissues take up the various components before the remnants return to the liver [4].

#### **3. Classification and composition of plasma lipoproteins**

Lipoproteins vary in size, density and composition which affects their functions, atherosclerotic risk profiles and other effects on health [3]. Based on major lipid and apolipoprotein content which determines their density, lipoproteins are classified into six categories; chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), lipoprotein (a) [Lp(a)], and high-density lipoprotein (HDL) (**Table 1**). Accompanying apolipoproteins and their functions are described in **Table 2**.

The main function of chylomicrons is the transport of dietary triglycerides from the intestine to the liver and other peripheral tissues, while VLDL particles carry endogenously synthesized triglycerides from the liver to other tissues. LDL particles are the major carriers of cholesterol in the circulation, supplying it to the cells, whereas the role of HDL is to transfer cholesterol from peripheral tissues to the liver.

**5**

**3.1 Chylomicrons**

**Table 2.**

*VLDL - very-low-density lipoprotein.*

*Major apolipoprotein characteristics.*

Chylomicrons are the largest particles in the lipoprotein family with the highest lipid to protein ratio. These triglyceride-rich particles contain apolipoproteins A-I, A-II, A-IV, A-V, B-48, C-II, C-III, and E, nevertheless, apo B-48 is the core structural protein and each chylomicron particle contains one Apo B-48 molecule [6]. The size of chylomicrons varies depending on the amount of fat ingested. A meal high in fat results in the formation of large chylomicron particles due to the increased quantity

*Dyslipidemia: Current Perspectives and Implications for Clinical Practice*

**TGs (%)**

Chylomicrons <0.95 80-100 90-95 2-4 2-6 1 ApoB-

*Apo - apolipoprotein; HDL - high-density lipoprotein; IDL - intermediate-density lipoprotein; LDL - low-density lipoprotein; Lp(a) - lipoprotein(a); PLs - phospholipids; TGs - triglycerides; VLDL - very low-density lipoprotein.*

**Cholesteryl esters (%)**

**PLs (%)**

30-80 50-65 8-14 12-16 4-7 ApoB-

25-30 25-40 20-35 16-24 7-11 ApoB-

20-25 4-6 34-35 22-26 6-15 ApoB-

intestine

Liver, intestine

Apo(a) Lp(a) Liver Component of Lp(a), links to LDL,

*Apo - apolipoprotein; HDL - high-density lipoprotein; IDL - intermediate-density lipoprotein; LCAT - lecithincholesterol acyltransferase; LDL - low-density lipoprotein; LPL - lipoprotein lipase; Lp(a) - lipoprotein (a);* 

Apo B-48 Chylomicrons Intestine Major component of chylomicron,

8-13 7 10-20 55 5 ApoA-I ApoA-II,

25-30 4-8 35-46 17-24 6-9 Apo(a) ApoB-100

LCAT

**Cholesterol (%)**

**Apolipoproteins Major Others**

> ApoA-I, II, IV, V

> ApoA-I, C-II, C-III, E, A-V

ApoC-II, C-III, E

C-II, E, M

48

100

100

100

Major component of HDL, activates

synthesized in the intestine

triglyceride hydrolysis

LDL receptor ligand

inhibits fibrinolysis

**Diameter (nm)**

*DOI: http://dx.doi.org/10.5772/intechopen.98386*

**(g/mL)**

1.006

1.019

1.063

1.210

1.125

*Physical and chemical characteristics of human plasma lipoproteins.*

Apo A-I HDL Liver,

Apo E Chylomicrons, remnants, VLDL, HDL

**Apolipoprotein Location Origin Function**

Apo A-II HDL Liver Component of HDL

Apo B-100 VLDL, IDL, LDL, Lp(a) Liver LDL receptor ligand

Apo C-III Chylomicrons, VLDL, HDL Liver Inhibits LPL

Apo C-II Chylomicrons, VLDL, HDL Liver co-factor for LPL, stimulates

**Lipoprotein Density** 

VLDL 0.95-

IDL 1.006-

LDL 1.019-

HDL 1.063-

Lp(a) 1.006-

*Adapted from Ref. [5].*

**Table 1.**


#### *Dyslipidemia: Current Perspectives and Implications for Clinical Practice DOI: http://dx.doi.org/10.5772/intechopen.98386*

*Apo - apolipoprotein; HDL - high-density lipoprotein; IDL - intermediate-density lipoprotein; LDL - low-density lipoprotein; Lp(a) - lipoprotein(a); PLs - phospholipids; TGs - triglycerides; VLDL - very low-density lipoprotein. Adapted from Ref. [5].*

#### **Table 1.**

*Management of Dyslipidemia*

**2. Lipids and lipoproteins**

prevention.

apolipoproteins.

binds to the low-density lipoprotein receptor).

remnants return to the liver [4].

metabolic derangements play in the pathogenesis of atherosclerosis paves the way for stronger implementation of current guidelines for CVD risk assessment and

Lipids are essential components of the human body, having several important biological functions such as storing energy, acting as structural components of cell membranes and participating in signaling pathways. The three main types of lipids are phospholipids, sterols, and triglycerides (also known as triacylglycerols) [3]. In view of the fact that the term "lipid" has been defined as any of a group of organic compounds that are insoluble in water but soluble in organic solvents, lipids comprise a broad range of molecules such as fatty acids, triglycerides (TG), phospholipids, sterols, sphingolipids and many others. However, from a clinical standpoint, given their role in the pathogenesis of CVD, the two major forms of circulating lipids in the body are TG and cholesterol. Although insoluble in plasma, these lipids can be transported throughout the bloodstream as lipoproteins when packaged with phospholipids and proteins known as apoproteins or

Lipoproteins are complex particles that have a central hydrophobic core composed of non-polar lipids, primarily cholesterol esters (CE) and TG and a hydrophilic surface consisting of polar lipids (phospholipids and free cholesterol) and apoproteins. The protein component provides structural integrity to the framework of the lipoproteins and being attached to the surface of particles, make them detectable for enzymes and receptors. Hence, apoproteins modulate enzyme activity (eg, apoprotein C-II activates lipoprotein lipase) and serve as ligands, specific recognition sites for cell surface receptors during cellular uptake (eg, apoprotein B-100

Lipoproteins are synthesized in both the liver and the intestines, playing a key role in the absorption and transport of dietary lipids by the small intestine, in the transport of lipids from the liver to peripheral tissues, and from peripheral tissues to the liver and intestine (a process known as reverse cholesterol transport). Within the circulation, lipoproteins go through constant change in composition and physical structure as the peripheral tissues take up the various components before the

Lipoproteins vary in size, density and composition which affects their functions, atherosclerotic risk profiles and other effects on health [3]. Based on major lipid and apolipoprotein content which determines their density, lipoproteins are classified into six categories; chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), lipoprotein (a) [Lp(a)], and high-density lipoprotein (HDL) (**Table 1**). Accompanying apoli-

The main function of chylomicrons is the transport of dietary triglycerides from the intestine to the liver and other peripheral tissues, while VLDL particles carry endogenously synthesized triglycerides from the liver to other tissues. LDL particles are the major carriers of cholesterol in the circulation, supplying it to the cells, whereas the role of HDL is to transfer cholesterol from peripheral tissues to

**3. Classification and composition of plasma lipoproteins**

poproteins and their functions are described in **Table 2**.

**4**

the liver.

*Physical and chemical characteristics of human plasma lipoproteins.*


*Apo - apolipoprotein; HDL - high-density lipoprotein; IDL - intermediate-density lipoprotein; LCAT - lecithincholesterol acyltransferase; LDL - low-density lipoprotein; LPL - lipoprotein lipase; Lp(a) - lipoprotein (a); VLDL - very-low-density lipoprotein.*

#### **Table 2.**

*Major apolipoprotein characteristics.*

### **3.1 Chylomicrons**

Chylomicrons are the largest particles in the lipoprotein family with the highest lipid to protein ratio. These triglyceride-rich particles contain apolipoproteins A-I, A-II, A-IV, A-V, B-48, C-II, C-III, and E, nevertheless, apo B-48 is the core structural protein and each chylomicron particle contains one Apo B-48 molecule [6]. The size of chylomicrons varies depending on the amount of fat ingested. A meal high in fat results in the formation of large chylomicron particles due to the increased quantity

of TG being transported whereas in the fasting state the chylomicron particles are smaller since they are carrying decreased amount of TG.

#### **3.2 Chylomicron remnants**

The removal of TG from chylomicrons by peripheral tissues results in smaller particles called chylomicron remnants. Compared to chylomicrons these particles are enriched in cholesterol and are pro-atherogenic [7].

#### **3.3 Very low-density lipoproteins (VLDL)**

Very low-density lipoproteins are also triglyceride-rich particles, however, they are smaller than chylomicrons and contain relatively less TG but more cholesterol and protein. Similar to chylomicrons the size of the VLDL particles vary depending on the amount of TG carried in the particle. Hence, when TG production in the liver is increased, the secreted VLDL particles are large. VLDL particles contain apolipoproteins B-100, C-I, C-II, C-III, and E. Apo B-100 is the core structural protein and each VLDL particle contains one Apo B-100 molecule [8].

### **3.4 Intermediate-density lipoproteins (IDL; VLDL remnants)**

The removal of TG from VLDL by peripheral tissue (muscle and adipose tissue) results in the formation of IDL particles which are enriched in cholesterol. These particles contain apolipoprotein B-100 and E and are pro-atherogenic [8].

### **3.5 Low-density lipoproteins (LDL)**

Low density lipoproteins are derived from VLDL and IDL particles by the lipoprotein lipase-mediated intravascular removal of TGs and are further enriched in cholesterol. Therefore, the LDL inner core is predominately composed of cholesterol esters. LDL particles are the primary transport mechanism for the delivery of cholesterol to peripheral tissues, accounting for the majority of circulating cholesterol in humans. Apo B-100 is the predominant structural protein and each LDL particle contains one Apo B-100 molecule [3]. LDL comprise a range of particles differing in size and density. Small dense LDL (sdLDL) particles are considered to be more atherogenic than larger LDL subfractions [9]. A growing body of evidence suggests that sdLDL particles have a decreased affinity for the LDL receptor resulting in a prolonged retention time in the circulation. Longer circulation times lead to multiple atherogenic modifications of sdLDL particles, further increasing its atherogenicity. Moreover, sdLDL particles bind more avidly to intraarterial proteoglycans and are characterized by the enhanced ability to enter the arterial wall. Finally, sdLDL particles are more susceptible to oxidation, which could result in an enhanced uptake by macrophages [10].

The predominance of sdLDL has been associated with hypertriglyceridemia, low HDL and high-hepatic lipase activity. This lipid phenotype was found to be present across the broad spectrum of metabolic disorders including obesity, metabolic syndrome, type 2 diabetes and is considered as a risk factor of coronary heart disease.

#### **3.6 High-density lipoproteins (HDL)**

High density lipoproteins are the smallest particles in the lipoprotein family composed of a relatively high proportion of protein thus having the lowest lipid to protein ratio. Their core is mainly composed of cholesterol esters. HDL particles

**7**

*Dyslipidemia: Current Perspectives and Implications for Clinical Practice*

varying in size, density and apolipoprotein composition.

contain apolipoproteins A-I, A-II, A-IV, C-I, C-II, C-III, and E. Apo A-I is the core structural protein and each HDL particle may contain multiple Apo A-I molecules. The main physiological role of HDL is in the transport of cholesterol from peripheral tissues to the liver, which is one possible mechanism to explain their ability to inhibit atherosclerosis [11]. In addition, HDL particles have anti-oxidant, antiinflammatory, anti-thrombotic, and anti-apoptotic properties, which may also contribute to their anti-atherogenic potential. HDL comprise a range of particles

Lipoprotein(a) consists of an LDL particle and the specific apolipoprotein(a),

which is attached via a single disulfide bond to the Apo B-100. Lp(a) contain Apo(a) and Apo B-100 in a 1:1 molar ratio. The structure of apolipoprotein(a) is similar to plasminogen and tissue plasminogen activator (tPA) containing multiple kringle repeats. Due to a variable number of kringle repeats, each of which consists of 114 amino acids, the molecular weight of apo(a) isoforms can range from 250,000 to 800,000 [12]. The production rate of Lp(a) is predominantly genetically determined resulting in highly variable Lp(a) plasma concentration ranging from undetectable to more than 200 mg/dl. There is a general inverse correlation between the Lp(a) concentration in plasma and the size of the apo(a) isoform. Individuals with low molecular weight Apo (a) tend to have higher levels while individuals with high molecular weight Apo(a) isoforms tend to have lower levels of Lp(a). It is hypothesized that the larger the isoform, the more Apo(a) precursor protein accumulates intracellularly in the endoplasmic reticulum and consequently the liver is less efficient in secreting high molecular weight Apo(a) [13]. The mechanism of Lp (a) clearance is still not fully elucidated but does not seem to include LDL receptors. As kidney disease is associated with an increase in Lp (a) levels, the kidney appears to have an important role in Lp (a) clearance. Elevated plasma Lp(a) levels are associated with an increased risk of atherosclerosis. There are several proposed mechanisms to explain a proatherogenic role of Lp(a). As the structure of Apo(a) is similar to plasminogen and tPA it competes with plasminogen for its binding site, leading to reduced fibrinolysis. Moreover, Lp(a) stimulates the secretion of PAI-1, which results in enhanced thrombogenesis. Also, Lp(a) particles are preferential carriers of atherogenic pro-inflammatory oxidized phospholipids in human plasma that attracts inflammatory cells to vessel walls and stimulate smooth muscle cell proliferation [14]. However, statin therapy as well as other therapies that accelerate

LDL clearance and decrease LDL levels do not decrease Lp(a) levels [15].

Consistent evidence from epidemiologic and clinical studies, supports the key role of the apoB containing lipoproteins in atherogenesis. All ApoB-containing lipoproteins with size less than 70 nm can cross the endothelial barrier, particularly in the presence of endothelial dysfunction [16]. Uptake and accumulation of apoBcontaining lipoproteins in the arterial wall is a critical initiating event in the development of atherosclerosis. Upon entry, apoB-containing lipoproteins are modified and oxidized into proinflammatory particles, which provoke the activation of the innate immune system within the arterial intima. The endothelial cells secrete adhesion molecules, and the smooth muscle cells (SMCs) secrete chemokines, which together attract monocytes and other immune cells into the arterial wall. When monocytes enter the subendothelial space, they transform into macrophages.

**4. The role of lipids and lipoproteins in atherogenesis**

*DOI: http://dx.doi.org/10.5772/intechopen.98386*

**3.7 Lipoprotein(a) [Lp(a)]**

#### *Dyslipidemia: Current Perspectives and Implications for Clinical Practice DOI: http://dx.doi.org/10.5772/intechopen.98386*

contain apolipoproteins A-I, A-II, A-IV, C-I, C-II, C-III, and E. Apo A-I is the core structural protein and each HDL particle may contain multiple Apo A-I molecules. The main physiological role of HDL is in the transport of cholesterol from peripheral tissues to the liver, which is one possible mechanism to explain their ability to inhibit atherosclerosis [11]. In addition, HDL particles have anti-oxidant, antiinflammatory, anti-thrombotic, and anti-apoptotic properties, which may also contribute to their anti-atherogenic potential. HDL comprise a range of particles varying in size, density and apolipoprotein composition.
