Chylomicrons properties

Disorders of lipoprotein metabolism involve perturbations which cause elevation of triglycerides and/or cholesterol, reduction of HDL-C, or alteration of properties of lipoproteins, such as their size or composition. These perturbations can be genetic (primary) or occur as a result of other diseases, conditions, or drugs (secondary). Some of the most important secondary disorders include hypothyroidism, diabetes mellitus, renal disease, and alcohol use. Hypothyroidism causes elevated LDL-C levels due primarily to downregulation of the LDL receptor. Insulin-resistance and type 2 diabetes mellitus result in impaired capacity to catabolize chylomicrons and VLDL, as well as excess hepatic triglyceride and VLDL production. Chronic kidney disease, including but not limited to end-stage... 

The overall metabolism of vitamin A in the body is regulated by esterases. Dietary retinyl esters are hydrolyzed enzymatically in the intestinal lumen, and free retinol enters the enterocyte, where it is re-esterified. The resulting esters are then packed into chylomicrons delivered via the lymphatic system to the liver, where they are again hydrolyzed and re-esterified for storage. Prior to mobilization from the liver, the retinyl esters are hydrolyzed, and free retinol is complexed with the retinol-binding protein for secretion from the liver [101]. Different esterases are involved in this sequence. Hydrolysis of dietary retinyl esters in the lumen is catalyzed by pancreatic sterol esterase (steryl-ester acylhydrolase, cholesterol esterase, EC 3.1.1.13) [102], A bile salt independent retinyl-palmitate esterase (EC 3.1.1.21) located in the liver cell plasma hydrolyzes retinyl esters delivered to the liver by chylomicrons. Another neutral retinyl ester hydrolase has been found in the nuclear and cytosolic fractions of liver homogenates. This enzyme is stimulated by bile salts and has properties nearly identical to those observed for... 

Lipoproteins are globular, micelle-like particles consisting of a hydrophobic core of triacylglycerols and cholesterol esters surrounded by an amphipathic coat of protein, phospholipid and cholesterol. The apolipoproteins (apoproteins) on the surface of the lipoproteins help to solubilize the lipids and target the lipoproteins to the correct tissues. There are five different types of lipoprotein, classified according to their functional and physical properties chylomicrons, very low density lipoproteins (VLDLs), intermediate density lipoproteins (IDLs), low density lipoproteins (LDLs), and high density lipoproteins (HDLs). The major function of lipoproteins is to transport triacylglycerols, cholesterol and phospholipids around the body. 

The chemical-physical properties of lipoproteins are listed in Table 19.1. It is seen that the density of lipoproteins is lowest for chylomicrons, followed by VLDL, IDL, LDL, and HDL. As density increases, the amount of lipid de-... 

Several types of proteins are associated with lipoproteins. These are termed apolipoproteins, or simply apoproteins. Table 19.2 shows the various apolipo-proteins (Apos), their chemical properties and occurrence, and their function, which is discussed later. Note that the A apoproteins are found largely in HDL, the B-100 is found largely in LDL, VLDL, and IDL, and C apoproteins are largely seen in chylomicrons. Nevertheless, there is a large degree of apoprotein overlap among the various lipoprotein classes. 

Blood plasma contains a number of soluble lipoproteins, which are classified, according to their densities, into four major types. These lipid-protein complexes function as a lipid transport system. Isolated lipids are insoluble in blood, but they are rendered soluble, and therefore transportable, by combination with specific proteins, the so-called lipoproteins. There are four basic types in human blood (1) chylomicrons, (2) very low density lipoproteins (VLDL), (3) low-density lipoproteins (LDL). and (4) high-density lipoproteins (HDL). Their properties are summarized in Table 6.2. 

See Fig. 6-4. The polar surface of the spherical particle renders the assembly soluble in water. This structure can be considered to be a tentative one only. The amount of polar material in chylomicrons and VLDL is astonishingly small. Moreover, when lipoproteins come into contact with the membranes of the cells of target tissue, the proteins remain soluble and do not become incorporated into the membrane. This suggests that the proteins of lipoproteins have unusual properties. It is known that several species of proteins (apoproteins AI, All. B4K, B1(K), Cl, CII, CIII, D, and E) occur. The amino acid sequences of some of them have been determined, and they possess hydrophobic regions i.e., they have properties suggesting that parts of their structure are compatible with hydrocarbons (e.g., TAGs and the tails of phospholipids). 

These lipids are insoluble in water and are classified on the basis of their ultracentrifugal properties into chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in order of ascending density. Table 2.4 gives the classification and roles of lipoproteins. 

Lipoproteins are assembled in two organs, the small intestine and the liver. The lipoproteins assembled in the intestine contain the lipids assimilated from the diet. These lipoproteins, called chylomicrons, leave the enterocyte and enter the bloodstream via the Lymphatic system. The lipoproteins assembled in the liver contain lipids originating from the bloodstream and from de novo synthesis in the liver. The term de novo simply means "newly made from simple components" as opposed to "acquired from the diet" or "recycled from preexisting complex components." These lipoproteins, called very-low-dcnslty lipoproteins (VLDLs), are secreted from the liver into the bloodstream. The liver also synthesizes and secretes other Lipoproteins called high-density Lipoproteins (HDLs), which interact with the chylomicrons and VLDLs in the bloodstream and promote their maturation and function. The data in Table 6-4 show that chylomicrons contain a small proportion of protein, whereas HDLs have a relatively high protein content. Of greater interest is the identity and function of the proteins that constitute these particles. These proteins confer specific properties to lipoprotein particles, as detailed later in this chapter. 

FAT EMULSION For parenteral nutrition a fat emulsion for intravenous administration is used. Preparations contain a fractionated soya-oil emulsified with some fractionated egg phospholipids. About 60% of the fatty acids are essential fatty acids the particle size and biological properties are similar to those in natural chylomicrones. 

Some cells have been observed to change the coding properties of newly synthesized mRNA molecules. In this process, called RNA editing, certain bases are chemically modified, deleted, or added. For example, the mRNA for apolipoprotein B-100 in liver cells codes for a 4563 amino acid polypeptide which is a component of very low density lipoprotein (VLDL). Intestinal cells produce a shorter version of the molecule called apolipoprotein B-48 (2153 amino acid residues) that becomes incorporated into the chylomicron particles produced by these cells. The cytosine in a CAA codon that specifies glutamine is converted by a deamination reaction into a uracil. The new codon, UAA, is a stop signal in translation hence a truncated polypeptide is produced during translation of the edited mRNA. 

An interesting discussion on surface properties of chylomicron particles has been given by Dole and Hamlin (1962). 

Although apoprotein A-IV exhibits the properties of an apolipoprotein [2], and recent data on its sequence [11, 12, 21] have shown that it contains 14.5 tandemly repeated docosapeptides that possess the potential to form amphipathic a-helices [11], it is mainly found unassociated with lipoproteins in human plasma [4,18,19,36]. The Apo A-IV fraction in the lipoprotein-free plasma compartment is still able to bind lipids, as shown by Weinberg and Scanu [37], who were able to reassociate Apo A-IV from the d = 1.21 g/ml infranate to a phospholipid-triglyceride emulsion. After reassociation Apo A-IV could be isolated by flotation in chylomicron-like particles upon ultracentrifugation. 

The possible mechanism of Apo A-IV displacement from the surface of chylomicrons upon entry into the plasma was studied in an in vitro model by Weinberg and Spector [41]. They used Apo A-IV associated with a phospholipid-triglyceride emulsion for displacement studies. When these chylomicron-like particles were incubated with HDL, they found a displacement of Apo A-IV from these particles, mainly by Apo C-III. Thus, one of the mechanisms responsible for the dissociation of Apo A-IV frbm chylomicrons upon entry into the plasma compartment could be a displacement by other circulating apoproteins that have a higher affinity for chylomicrons (or their remnants after attack by hpoprotein lipase). In contrast to Apo A-IV, which decays and is later mostly found in the lipoprotein-free plasma compartment, the other major chylomicron apoprotein, A-I, reassociates with HDL, as shown by tracer kinetic studies [20, 29]. It thus remains puzzling why the bulk of Apo A-IV, despite its apoprotein structure, does not reassociate with lipoproteins. In addition, lymph and plasma Apo A-IV have similar a-helical contents and properties in solution [10]. This seems to be an unexplained phenomenon since we were able to show that apoprotein A-IV, isolated either from chylomicrons or from lipoprotein-free plasma, recombines with hpids to form stable complexes [34]. 

The metabolism of lipid emulsions has long been considered to be similar to that of chylomicrons with intravascular lipolysis by lipoprotein lipase (LPL) being followed by tissue uptake of remnant particles. However, other studies have suggested that lipid emulsions are cleared from blood with less lipolysis than chylomicrons and that a substantial number of emulsions can be cleared as almost intact whole particles by different tissues. The metabolism of lipid emulsions is affected by many factors, including triglyceride (TG) composition. For example, MCT LCT emulsions are cleared faster from blood than pure LCT emulsions. Recently, it was reported that pure FO emulsion particles are removed from blood faster and by different pathways as compared with LCT emulsions. Removal of LCT emulsions is modulated by LPL, apolipoprotein E (apoE), LDL receptor (LDL-R), and lactoferrin-sensitive pathways. In contrast, clearance of FO emulsions relies on LPL to a much lesser extent and is apparently independent of apoE, LDL-R, and lactoferrin-sensitive pathways. It can therefore be noted that the materials selecteds to develop a nanoemulsion composition may not only affect the physicochemical properties and stability of the formulation but may alter significantly the biofate and efficacy of the nanoemulsions. 

---