Textbook - BIOLOGICAL CHEMISTRY - Hubsky Yu.I. - 2000

Chapter III. METABOLISM OF MAJOR CLASSES OF BIOMOLECULES

CHAPTER 16. LIPID METABOLISM. III. CHOLESTEROL METABOLISM. LIPID TRANSPORT

16.3. TRANSPORT AND STORAGE OF LIPIDS. PLASMA LIPOPROTEINS. HYPERLIPOPROTEINEMIAS

Various classes of dietary Lipids enter The Human Body, namely: triacylglycerols (which constitute the bulk of dietary fats); free Cholesterol and its fatty acid esters (cholesteryl esters); and Complex Lipids (predominantly Glycerophospholipids).

The Biochemical Mechanisms of Digestion of various lipid classes in the human gastrointestinal tract will be covered in detail in Chapter 26. This chapter examines the main processes involved in the biotransport of triacylglycerols and cholesterol, starting with the absorption of these lipids by the intestinal mucosa.

Under the action of pancreatic lipase and with the participation of Bile acids produced in the Liver, dietary triacylglycerols are hydrolyzed to yield 2-monoacylglycerols (monoglycerides) and two molecules of free Fatty acids, which can be represented by the following overall equation:

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These Hydrolysis products (Higher Fatty Acids, monoglycerides) are absorbed by the Cells of the small intestinal mucosa (enterocytes). Dietary cholesterol is absorbed in a free state, whereas cholesteryl esters are absorbed after appropriate hydrolysis by cholesterol esterase.

Inside the enterocytes, the absorbed products of triacylglycerol hydrolysis participate in two biochemical processes that are Prerequisites for the subsequent entry of neutral fats into the bloodstream, biotransport, and their tissue storage, namely:

- re-Esterification of higher fatty acids to form new triacylglycerol molecules;

- formation of transport forms of triacylglycerols, known as chylomicrons.

Resynthesis of Triacylglycerols in Enterocytes

Since 2-monoacylglycerols are the primary products of triacylglycerol hydrolysis absorbed by intestinal epithelial cells, the re-esterification of fatty acids within these cells proceeds via the monoglyceride pathway, which includes the following reactions:

1. Formation of 1,2-monoacylglycerols (catalyzed by the intestinal enzyme monoacylglycerol acyltransferase):

2. Formation of triacylglycerols involving diacylglycerol acyltransferase:

Formation of Chylomicrons

Triacylglycerols are resynthesized in The Endoplasmic reticulum of the mucosal cells of the Small Intestine. They form ultramicroscopic droplets coated with a layer of surface-active Proteins and Phospholipids. These structures are called chylomicrons. Chylomicrons also contain free and esterified cholesterol.

Chylomicrons serve as the primary molecular form through which neutral fats (triacylglycerols) pass across the basolateral membrane of enterocytes and, via the lymphatic vessel system (lacteals), enter the Thoracic duct and subsequently the Blood Circulation (via the left subclavian vein).

Plasma Lipoproteins

In addition to chylomicrons, human blood contains several classes of lipid-Structure/178.html">Protein Complexes that perform the function of interorgan lipid transport—plasma transport lipoproteins. Transport lipoproteins represent the physicochemical mechanism by which hydrophobic lipid molecules are maintained in a stable state within the hydrophilic (aqueous-salt) environment of Blood Plasma.

Fractionation of human blood lipoproteins is performed using plasma ultracentrifugation in salt solutions, during which differential flotation of various lipoprotein classes occurs, depending on their particle size and density. Lipoproteins can also be separated by Electrophoresis, migrating alongside specific globulin classes (such as α- and β-lipoproteins).

The modern clinical and biochemical Classification of human plasma lipoproteins is based on their Separation by ultracentrifugation. There is a definite correspondence between the lipoprotein classes separated using these two Fractionation Methods.

Main classes of human blood plasma lipoproteins.

- chylomicrons (CM);

- very low-density lipoproteins (VLDL), or pre-β-lipoproteins;

- intermediate-density lipoproteins (IDL);

- low-density lipoproteins (LDL), or β-lipoproteins;

- high-density lipoproteins (HDL), or α-lipoproteins.

These lipoprotein classes differ in their physicochemical characteristics (Table 16.1), biochemical (lipid and protein) composition, and physiological Functions.

Table 16.1. Physical Properties of human blood plasma lipoproteins

In terms of molecular structure, blood plasma lipoproteins are spherical structures—micelles, containing a hydrophobic lipid core inside, which consists mainly of triacylglycerols and cholesterol esters. The Hydrophobic core is coated with a layer of polar amphipathic phospholipids, peripheral, and integral proteins. The molecular Structure of Lipoproteins is shown in Fig. 16.4.

Fig. 16.4. Cytology/cytology/92.html">SCHEMATIC STRUCTURE OF blood plasma lipoproteins.

Individual lipoprotein classes also differ in the composition of their constituent proteins. The proteins that make up human blood plasma lipoproteins are called apolipoproteins (apoproteins, apoprotides, apo). There are five main families of such proteins (A, B, C, D, E), which include ten major apoproteins: A-1, A-2, A-4, B-48, B-100, C-1, C-2, C-3, D, and E, which are part of specific lipoproteins in various quantitative ratios (Table 16.2).

Table 16.2. Human blood plasma apolipoproteins

Lipoproteins of certain classes (LPs) contain varying amounts of individual blood lipid fractions—triacylglycerols (TG), free ($C_f$) and esterified ($C_e$) cholesterol, phospholipids (PL)—in the inter-organ transport of which they actively participate (Table 16.3). These lipoproteins are formed in various Organs, and their METABOLISM is of paramount importance for the normal distribution and storage of Neutral Fats and cholesterol.

Table 16.3. Chemical composition of major human blood plasma lipoproteins (%) (after R. Murray et al., 1988; L. Stryer, 1995)

Chylomicrons are lipoproteins formed in the mucous membrane of the small intestine following the intracellular resynthesis of triacylglycerols. They serve as the molecular form by which neutral fats and cholesterol pass from enterocytes into the bloodstream via The Lymphatic system.

VLDL are lipoproteins that also contain a significant amount of neutral fats. VLDL are synthesized in hepatocytes and represent the primary molecular form in which triacylglycerols exit the liver into the blood and are transported to other organs. A certain amount of VLDL is formed, similar to chylomicrons, in enterocytes during dietary Lipid Digestion and enters the blood from the intestine.

Chylomicrons and VLDL daily transport an average of 70-150 g of neutral fats from the intestine and liver to various Tissues (adipose tissue, etc.). The tissue deposition of triacylglycerols transported by blood plasma lipoproteins is facilitated by lipoprotein lipase of the vascular endothelium in various organs, which hydrolyzes the neutral fats found within CM and VLDL.

Lipoprotein lipase is an enzyme protein adsorbed onto glycosaminoglycans on the endothelial surface, featuring a blood lipoprotein-binding center and a catalytic center for triacylglycerol hydrolysis. Under the action of lipoprotein lipase, free Fatty Acids and glycerol are formed, penetrating the vascular wall into cells, where they are either oxidized to release energy (in myocytes, etc.) or stored as reserve triacylglycerols (in adipocytes of adipose tissue). The lipoproteins formed As a result of CM and VLDL delipidation are remnant lipoproteins, enriched (compared to CM and VLDL) in free and esterified cholesterol.

CM remnants are cleared from the blood by liver cells, which utilize most of the cholesterol from these lipoproteins to synthesize bile acids. VLDL remnants are called IDL and serve as direct precursors in LDL formation.

LDL are lipoproteins formed from IDL (VLDL remnants) under the action of hepatic lipase, localized on the luminal surface of liver endothelial cells. The resulting LDL contain, unlike their precursors—VLDL and IDL—a significantly smaller amount of triacylglycerols and differ in their apoprotein composition. At the same time, LDL contain the highest amount of cholesterol (mostly in esterified form), making them the main class of human blood plasma lipoproteins that transport cholesterol.

LDL are taken up by cells of various organs via pinocytosis following the interaction of these lipoproteins with LDL-specific receptors on Plasma Membranes. Due to these receptors, LDL fulfill their function as the primary molecular vehicle for cholesterol transport into tissues.

The Biological Role of LDL receptors is to ensure that all cells in the body are supplied with an adequate amount of cholesterol, which is essential for building Introduction/36.html">Biological Membranes and synthesizing physiologically active products of cholesterol biotransformation, such as bile acids, Sex Hormones, and corticosteroids. Accordingly, the highest concentration of LDL receptors is found on the plasma membranes of cells in the liver, Gonads, and Adrenal Glands.

Impaired LDL metabolism serves as the biochemical basis for several severe Lipid Metabolism disorders. Since cholesterol can penetrate the vascular wall specifically as a component of LDL, high concentrations of these lipoproteins in human blood plasma are considered a major risk factor for atherosclerosis (see below). A genetically inherited defect in LDL receptor synthesis leads to familial hypercholesterolemia (FH), which manifests as LDL accumulation in the plasma and marked hypercholesterolemia starting in early childhood. For their discovery of LDL receptors and elucidation of the molecular mechanisms underlying FH, American scientists M. Brown and J. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine.

HDLs are lipoproteins synthesized in The Liver and, to some extent, in the small intestine as bilayer lipid discs consisting primarily of phospholipids, free cholesterol, and the apolipoproteins Apo E and Apo C. Maturation of these lipoproteins occurs in the blood, where Apo E and Apo C are replaced by Apo A, cholesterol is esterified through the action of lecithin-cholesterol acyltransferase, and the lipoprotein particles acquire a spherical shape. Based on their chemical composition, HDLs are divided into subclasses: HDL₂ and HDL₃.

Similar to LDLs, HDLs are capable of actively exchanging their cholesterol with the cholesterol integrated into Biomembranes. This process generates opposing flows of cholesterol: while LDLs deliver cholesterol into Cell membranes, HDLs, conversely, extract membrane cholesterol. Thus, HDLs counteract the excessive accumulation of cholesterol in cells, which is why they are regarded as antiatherogenic lipoproteins. HDL Catabolism also takes place in the liver.

Hyperlipoproteinemias

Hyperlipoproteinemia is a clinical and biochemical syndrome characterized by an elevated concentration (relative to the normal range for a given population) of specific classes of lipoproteins, as well as triacylglycerols and cholesterol, in human blood plasma.

Based on their origin, hyperlipoproteinemias are classified into:

- primary (inherited) hyperlipoproteinemias, which are caused by Genetic Defects in the synthesis of certain Enzymes involved in blood lipid metabolism (such as lipoprotein lipase or cholesterol acyltransferase) or non-enzymatic proteins, including defects in the Synthesis of specific apoproteins, apoprotein receptors, and lipoprotein receptors (particularly LDL receptors);

- secondary (acquired) hyperlipoproteinemias, which develop as a consequence of specific internal organ disorders (hepatitis, liver cirrhosis, nephrosis), endocrinopathies (thyroid or gonadal dysfunction, Diabetes Mellitus), or environmental damaging factors (chronic alcoholism).

The modern WHO classification of hyperlipoproteinemias takes into account the clinical and Biochemical characteristics of human lipid metabolism disorders (specifically the concentrations of LDL, VLDL, triacylglycerols, and cholesterol) regardless of their underlying causes, whether primary (genetic) or secondary. According to the WHO classification, there are five MAIN TYPES OF hyperlipoproteinemias (I, II, III, IV, V) and two subtypes (IIa and IIb), as presented in Table 16.4.

Table 16.4. WHO Classification of Hyperlipoproteinemias (after G. Thompson, 1991)

Examples of primary hyperlipoproteinemias that can be assigned to specific lipoprotein metabolism disorder types according to the WHO classification include:

- familial hypertriglyceridemia (familial chylomicronemia) — Type I;

- familial hypercholesterolemia (familial hyperbetalipoproteinemia) — Type II;

- familial dysbetalipoproteinemia — Type III;

- familial hyperprebetalipoproteinemia — Type IV.