Lipoproteins are macromolecular complexes consisting of a hydrophobic core formed by nonpolar lipids, mainly cholesterol esters and triglycerides, surrounded by a hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins (or apoproteins).

Based on the size, lipid, and apoprotein composition, lipoproteins are divided into seven classes (Table 1 and Fig.1):

– Chylomicrons

– Chylomicron remnants

– Very low-density lipoprotein (VLDL)

– Intermediate-density lipoprotein (IDL)

– Low-density lipoprotein (LDL)

– High-density lipoprotein (HDL)

– Lipoprotein(a) [Lp(a)]

Chylomicron remnants, VLDLs, IDLs, LDLs, and Lp(a), are proatherogenic lipoproteins, whereas HDLs are antiatherogenic.

Table1. Characteristics of lipoproteins

Fig1. Composition of plasma lipoproteins. HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; Lp (a), lipoprotein (a); VLDL, very low-density lipoprotein. EC, esterified cholesterol; FC, free cholesterol; TG, triglycerides; PL, phospholipids (Copyright EDISES 2021. Reproduced with permission)

Chylomicrons and Chylomicron Remnants

Chylomicrons are the largest lipoproteins synthesized at the intestinal level, with the primary role of transporting fats of exogenous origin, mainly triglycerides, absorbed at the enterocyte level, to the liver and peripheral tissues.

Among the apolipoproteins constituting chylomicrons, ApoB-48 represents the most important isoform, having not only a structural but also a functional role as it mediates the exocytosis of the particle from the enterocyte. A defect in ApoB-48, both qualitatively and quantitatively, limits the release of chylomicrons leading to enterocyte thesaurismosis. The size of chylomicrons varies according to the amount of ingested fat. A high-fat meal leads to large chylomicrons, whereas the fasting state results in small particles. The neo synthesized chylomicrons are secreted into the lymphatic circulation and then released through the thoracic duct into the systemic circulation. In this way, chylomicrons do not reach the liver directly via the portal circulation, thus avoiding an overload of fat that could lead to hepatic steatosis. In circulation, the triglycerides removal from chylomicrons by endothelial lipases leads to smaller particles, known as chylomicron remnants. Compared to chylomicrons, remnants are enriched in cholesterol and are proatherogenic.

VLDL and IDL

VLDLs are the very low-density lipoproteins synthesized in the liver. They represent the main plasma transport vehicle of endogenous triglycerides. The most represented apolipoprotein is ApoB-100. Similar to chylomicrons, the size of VLDL can vary depending on the number of triglycerides trans ported by the particle.

As soon as they are synthesized in the hepatocytes, VLDLs are released into the circulation, where they interact with lipoprotein lipases which, through the hydrolysis of triglycerides, cause their conversion first into IDL and then into LDL.

LDL

LDLs, the low-density lipoprotein, originate from IDL and have a high cholesterol content. Indeed, their main function is the transport of cholesterol in the plasma, both in free and esterified form.

Like VLDL, the major apolipoprotein in LDL is ApoB- 100, which plays a key role as it mediates the interaction of the lipoprotein with its receptor expressed on the cell membrane.

When LDLs are in plasma at high concentrations, they are potentially atherogenic. Indeed, they can passively diffuse through the junctions of endothelial cells and accumulate in the intima, triggering an inflammatory response. Under these conditions, LDL undergoes a process of oxidation; oxidized LDL is phagocytized by macrophages, which progressively turn into “foamy cells,” typical of both early and late atherosclerotic lesions. The accumulation of intracellular cholesterol does not negatively regulate macrophages; therefore, they continue to internalize oxidized LDL until they undergo apoptosis or necrosis, thus contributing to the formation, within the plaque, of a soft and destabilizing necrotic core rich in lipids.

LDL consists of a spectrum of particles that vary in size and density. Small and dense LDL is considered the most atherogenic for several reasons. First, small and dense LDL has a lower affinity for the LDL receptor prolonging the lipoprotein’s stay in the bloodstream. In addition, they penetrate the artery wall more easily, where they bind more avidly to proteoglycans and become trapped. Finally, they are more susceptible to oxidation resulting in greater uptake by macrophages.

HDL

 HDLs, the high-density lipoprotein, acts as a scavenger, mediating the cholesterol transport, from peripheral tissues to the liver. Nascent HDLs, synthesized in the liver and intestine, known as pre-beta HDLs, pick up free cholesterol at the periphery through interaction with the ABCA1 (ATP- Binding Cassette transporter A1) enzyme, and esterify it through the membrane-associated LCAT (lecithin- cholesterol acyltransferase) enzyme. The main inducer of the LCAT enzyme is ApoA-I apolipoprotein, which represents the most abundant protein component of HDL. The continuous accumulation of esterified cholesterol in the lipoprotein core transforms the nascent HDL from discoidal particles to spherical parts, called HDL-3. Through the esterified cholesterol transfer protein (CETP), HDL gives up esterified cholesterol, in exchange for triglycerides, to VLDL, IDL, and chylomicrons and is transformed into HDL-2. The latter, enriched in triglycerides, can be metabolized by hepatic and lipoprotein lipase and, thus, return to the nascent HDL stage, or be directly captured and degraded by the liver. The accelerated catabolism of tri glyceride-rich HDL-2 explains the common finding of low HDL cholesterol levels during hypertriglyceridemia.

Lp(a)

Lipoprotein(a) is synthesized in the liver and it is structurally similar to LDL, consisting of an ApoB-100 molecule covalently linked, by disulfide bridges, to apolipoprotein(a). Apo(a) has a molecular weight related to the number of repeated sequences (kringles), which varies widely in the population between 300 and 800 kDa. This variability is genetically determined and influences Lp(a) levels: low molecular weight isoforms are associated with high plasma Lp(a) levels and viceversa. In addition, the Apo(a) structure has a high homology with plasminogen.

The physiological role of Lp(a) is not yet completely clear, but levels >30 mg/dL are associated with an increased atherosclerotic risk. It is not known whether Lp(a) participates directly or indirectly in the formation of atheroma. However, due to its homology with plasminogen, Apo(a) may inhibit fibrinolysis and promote thrombosis, thus inter acting with the physiological mechanism of coagulation.

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