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

*Management of Dyslipidemia*

**3.2 Chylomicron remnants**

of TG being transported whereas in the fasting state the chylomicron particles are

The removal of TG from chylomicrons by peripheral tissues results in smaller particles called chylomicron remnants. Compared to chylomicrons these particles

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

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].

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

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.

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

smaller since they are carrying decreased amount of TG.

are enriched in cholesterol and are pro-atherogenic [7].

each VLDL particle contains one Apo B-100 molecule [8].

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

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

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

enhanced uptake by macrophages [10].

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

**6**

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].
