BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

CHAPTER 8. LIPID METABOLISM

The term "Lipids" encompasses a diverse group of compounds united by a shared physical property: Structure/106.html">Hydrophobicity, or Water-insolubility. Structurally, lipids are so varied that they lack any single common chemical feature. They are classified into groups comprising molecules with similar chemical structures and shared biological properties.

The bulk of lipids in the body consists of fats—triacylglycerols—which serve as an energy storage depot. Located primarily in subcutaneous adipose tissue, fats also provide thermal insulation and mechanical protection.

Phospholipids form a major Class of lipids, named for the phosphoric acid residue that imparts amphiphilic properties to them. Owing to this property, phospholipids form the bilayer structure of Introduction/36.html">Biological Membranes in which Proteins are embedded. Cells and intracellular compartments enclosed by membranes differ in composition and molecular makeup from their surrounding environment; consequently, chemical processes within The Cell are compartmentalized and spatially oriented, which is essential for the REGULATION OF METABOLISM.

Steroids, represented in the animal kingdom by Cholesterol and its derivatives, perform a wide range of Functions. Cholesterol is a crucial membrane component and a regulator of hydrophobic layer properties. Cholesterol derivatives (Bile acids) are essential for fat Digestion. Steroid Hormones, synthesized from cholesterol, participate in regulating Energy Metabolism, water-salt balance, and reproductive functions. In addition to steroid hormones, many lipid derivatives act as regulatory agents, functioning at extremely low concentrations just like hormones. For instance, platelet-activating factor, a uniquely structured phospholipid, profoundly influences platelet aggregation at a concentration of 10^-12 M; Eicosanoids, which are derivatives of polyunsaturated Fatty acids produced by nearly all cell types, elicit diverse biological effects at concentrations not exceeding 10^-9 M. These Examples illustrate the exceptionally broad spectrum of biological functions fulfilled by lipids.

In human tissues, the relative proportions of various lipid classes differ significantly. In adipose tissue, fats account for up to 75% of dry weight. In Nervous Tissue, lipids comprise up to 50% of dry weight, with the major constituents being phospholipids and sphingomyelins (30%), cholesterol (10%), and gangliosides and cerebrosides (7%). In a healthy Liver, the total lipid content normally does not exceed 10 — 13%.

Disorders of Lipid Metabolism lead to The Development of numerous pathologies, among which obesity and atherosclerosis are the most prevalent in human populations.

I. Structure, Classification, and Properties of Major Lipids in the Human Body

Different classes of lipids vary substantially in their STRUCTURE AND FUNCTIONS. The majority of lipids contain fatty acids linked via ester bonds to glycerol or cholesterol, or via an amide bond to the amino alcohol sphingosine.

A. Structure, Composition, and Properties of Fatty Acids and Acylglycerols

Fatty acids in The Human Body possess an even number of carbon atoms, a characteristic stemming from their Biosynthesis pathway, in which two-carbon fragments are sequentially added to a growing hydrocarbon radical.

Fatty acids serve as Structural components of various lipids. Within triacylglycerols, fatty acids function as energy reserves because their hydrocarbon chains contain energy-rich CH₂ groups. The oxidation of CH bonds yields more energy than the oxidation of CARBOHYDRATES, whose carbon atoms are already partially oxidized (-HСОН-). Within Phospholipids and Sphingolipids, fatty acids form the internal Hydrophobic core of membranes, determining its biophysical properties. Body fats and phospholipids maintain a liquid consistency at normal body Temperature because Unsaturated fatty acids predominate over saturated ones. Membrane phospholipids may contain up to 80 — 85% unsaturated fatty acids, whereas subcutaneous fat contains up to 60%.

Free, unesterified Fatty acids are present in the body in small amounts—for example, in the bloodstream, where they are transported in a complex with the protein albumin.

Human tissue fatty acids consist of unbranched hydrocarbon chains with a carboxyl group at one end and a methyl group (the ω-carbon atom) at the other. Most fatty acids in the body contain an even number of carbon atoms, ranging from 16 to 20 (Tables 8-1 and 8-2). Fatty acids lacking double bonds are termed saturated. The predominant saturated fatty acid in human lipids is palmitic acid (accounting for up to 30 — 35%). Fatty acids containing double bonds are designated as unsaturated. Unsaturated fatty acids include monoenoic acids (containing a single double bond) and polyenoic acids (containing two or more double bonds). When a fatty acid contains two or more double bonds, they are typically separated by a CH₂ group. There are several ways to depict fatty acid structures. When designating a fatty acid with a numerical symbol (Table 8-1, second Column), the total number of carbon atoms is written before the colon, followed by the number of double bonds after the colon. THE POSITION OF a double bond is indicated by the symbol Δ, followed by the number of the carbon atom closest to the carboxyl group where the double bond begins. For example, C18:1Δ9 indicates that the fatty acid contains 18 carbon atoms and a single double bond situated at the 9th carbon atom, counting from the carboxyl carbon. The position of a double bond can also be denoted relative to the methyl ω-carbon atom of the fatty acid chain. For instance, linoleic acid can be represented as C18:2Δ9,12 or C18:2ω-6. Based on the position of the first double bond from the terminal methyl carbon, polyunsaturated fatty acids are categorized into ω-3 and ω-6 families.

Table 8-1. Structure of Fatty Acids

Notes: Cn : m — number of carbon atoms (n) and number of double bonds (m) in the fatty acid molecule; w (6, 3) — position of the carbon atom of the first double bond, counting from the w- (methyl) carbon atom; D — position of the double bond, counting from the primary carboxyl carbon atom; * — fatty acids not synthesized in the body (Essential Fatty Acids); ** — arachidonic acid can be synthesized from linoleic acid.

Table 8-2. Fatty Acid Composition of Human Subcutaneous Fat

Double bonds in human fatty acids exhibit a cis-configuration, meaning that the acyl chains lie on the same side of the double bond. The cis-configuration introduces a kink into the aliphatic chain of the fatty acid, which disrupts the orderly packing of saturated fatty acid radicals within membrane phospholipids (Fig. 8-1) and lowers the melting point. The greater the number of double bonds in Lipid Fatty Acids, the lower their melting point. Table 8-1 highlights the principal fatty acids found in human lipids.

Fig. 8-1. Configurations of fatty acid radicals. A — kinking of the fatty acid radical caused by a cis-configuration double bond; B — disruption of the orderly packing of saturated fatty acid radicals in the hydrophobic core of membranes by an unsaturated acid with a cis-double bond.

Fatty acids with a trans-configuration of double bonds can enter the body through the diet, such as in margarine. These acids lack the kink characteristic of cis-bonds; consequently, fats containing such unsaturated acids possess higher melting points and firmer consistencies.

Most fatty acids can be synthesized within the human body; however, polyenoic acids (linoleic and α-linolenic) cannot be synthesized endogenously and must be obtained from dietary sources. These fatty acids are designated as essential fatty acids. The primary dietary sources of polyunsaturated fatty acids for humans are liquid vegetable oils and fish oils, which are rich in ω-3 family acids (Tables 8-1, 8-3).

Acylglycerols are esters of the trihydric alcohol glycerol and fatty acids. Glycerol can be linked to one, two, or three fatty acids, thereby forming mono-, di-, or triacylglycerols (MAG, DAG, TAG). The bulk of lipids in the human body consists of triacylglycerols, commonly known as fats. A normal human with a body weight of 70 kg contains up to 10 kg of fats. They are stored in adipose cells, or adipocytes, and serve as an energy source during fasting.

Mono- and diacylglycerols are formed as intermediates during the breakdown and synthesis of triacylglycerols. Because the carbon atoms in glycerol are oriented differently in space (Fig. 8-2), Enzymes distinguish between them and specifically attach fatty acids to the first, second, and third carbon atoms.

Fig. 8-2. Spatial arrangement of glycerol carbon atoms.

Nomenclature and composition of natural triacylglycerols. Natural fat molecules contain various fatty acids. As a rule, positions 1 and 3 contain more saturated fatty acids, whereas position 2 contains a polyenoic acid. The name of a triacylglycerol lists the fatty acid radicals starting from the first carbon atom of the glycerol backbone; for example, palmitoyl-linolenoyl-oleoylglycerol.

Fats containing predominantly saturated acids are solid (such as beef and mutton tallow), whereas those containing a high proportion of unsaturated acids are liquid. Liquid fats, or oils, are typically of plant origin (Table 8-3).

Table 8-3. Fatty acid composition and melting points of certain dietary fats

Notes: tr. — acids present in insignificant (trace) amounts. In addition to the indicated acids, fish oil contains up to 10% of 22:5 fatty acid (clupanodonic acid) and up to 10% of 22:6 (cervonic acid), which are essential for The formation of phospholipid structures in the human Nervous system. They are virtually absent in Other types of natural fats; * - fatty acids with 4 to 10 carbon atoms are found mainly in milk lipids.

Among dietary animal fats, mutton tallow is the most saturated and practically lacks essential fatty acids. Valuable dietary fats include fish oil and vegetable oils, which contain essential fatty acids. In marine fish, ω-3 and ω-6 polyunsaturated fatty acids are also not synthesized; fish acquire them through their diet (Algae, plankton).

B. Structure and Classification of phospholipids and sphingolipids

Phospholipids are a diverse group of lipids containing a phosphoric acid residue. They are subdivided into Glycerophospholipids, based on the trihydric alcohol glycerol, and sphingophospholipids, which are derivatives of the amino alcohol sphingosine. Phospholipids exhibit amphiphilic properties because they contain aliphatic fatty acid radicals and various polar groups. Owing to these properties, phospholipids not only form The basis of all cell membranes but also perform other functions: they form the surface hydrophilic layer of Blood Lipoproteins and coat the alveolar surface, preventing the walls from collapsing during expiration. Some phospholipids participate in hormone signal Transduction within cells. Sphingomyelins are phospholipids that form The structure of myelin sheaths and other Membrane structures in Nerve Cells.

Glycerophospholipids. The structural backbone of glycerophospholipids is glycerol. Glycerophospholipids (formerly called phosphoglycerides or phosphoacylglycerols) are molecules in which two fatty acids are esterified to glycerol at the First and Second positions; the third position contains a phosphoric acid residue, to which various substituents—most commonly amino alcohols—can be attached (Table 8-4, Fig. 8-3). When the third position contains only phosphoric acid, the glycerophospholipid is called phosphatidic acid. Its residue is termed "phosphatidyl" and forms part of the names of other glycerophospholipids, followed by the name of the substituent replacing the hydrogen atom in the phosphoric acid group, for example, phosphatidylethanolamine, phosphatidylcholine, etc.

Table 8-4. Classification of glycerophospholipids and sphingolipids

* Sphingomyelins are classified as both phospholipids and sphingolipids.

Fig. 8-3. Major glycerophospholipids in the human body.

Free Phosphatidic acid is present in small quantities in the body (see Chapter 5, Table 5), but it serves as an intermediate in the biosynthesis pathways of both triacylglycerols and glycerophospholipids. Like triacylglycerols, glycerophospholipids predominantly contain polyunsaturated acids at the second position; in the phosphatidylcholine molecule found in membrane structures, this is most frequently arachidonic acid. The fatty acids of membrane phospholipids differ from other human lipids by a high proportion of polyunsaturated acids (up to 80–85%), which maintains the fluid state of the hydrophobic layer required for the function of membrane-associated proteins.

Plasmalogens. Plasmalogens are phospholipids in which the first position of glycerol is linked not to a fatty acid, but to a long-chain aliphatic alcohol residue via an ether bond.

A characteristic feature of plasmalogens is a double bond between the first and second carbon atoms of the alkyl group (Fig. 8-4). There are Three types of plasmalogens: phosphatidylethanolamines, phosphatidylcholines, and phosphatidylserines. Plasmalogens account for up to 10% of the phospholipids in nervous tissue membranes; they are particularly abundant in the myelin sheaths of nerve cells.

Fig. 8-4. Plasmalogens.

Certain types of plasmalogens elicit potent biological effects by acting as mediators. For example, platelet-activating factor (PAF) stimulates platelet aggregation. PAF differs from other plasmalogens by lacking a double bond in the alkyl radical and possessing an acetyl group at the second position of glycerol instead of a fatty acid.

PAF is released from phagocytic Blood Cells in response to stimulation and promotes platelet aggregation, thereby participating in blood clotting. This factor is also responsible for the development of certain inflammatory and allergic manifestations.

Sphingolipids

The 18-carbon amino alcohol sphingosine contains hydroxyl groups and an amino group. Sphingosine forms a large group of lipids in which a fatty acid is attached to it via the amino group. The product of the interaction between sphingosine and a fatty acid is called a ceramide (Fig. 8-5). In ceramides, fatty acids are linked by an unusual (amide) bond, while the hydroxyl groups are capable of interacting with other radicals. Ceramides differ in the fatty acid radicals that make up their composition. Typically, these are long-chain fatty acids ranging from 18 to 26 carbon atoms in length.

Fig. 8-5. Sphingosine derivatives: ceramide and sphingomyelin.

Sphingomyelins. Sphingomyelin is formed by attaching phosphoric acid linked to Choline to the OH group of a ceramide (Fig. 8-5). Sphingomyelins are major components of myelin and the membranes of Brain and Nerve Tissue cells. Like glycerophospholipids, sphingomyelins exhibit amphiphilic properties due to, on the one hand, the fatty acid radical and the aliphatic chain of sphingosine itself, and on the other hand, the polar phosphorylcholine region.

Glycolipids. Ceramides serve as the foundation for a large group of lipids known as glycolipids (see Table 8-4 above). Hydrogen in the hydroxyl group of a ceramide can be replaced by various carbohydrate fragments, which determines the glycolipid's classification into a specific group. Glycolipids are found primarily in the membranes of neural tissue cells. The names "cerebrosides" and "gangliosides" reflect the tissues from which they were first isolated.

Cerebrosides. Cerebrosides contain Monosaccharides in their structure. The most common cerebrosides contain galactose (galactocerebroside), and less frequently, glucose (glucocerebroside). Cerebrosides contain unusual fatty acids; for example, the galactocerebroside phrenosin contains cerebronic acid, a 24-carbon 2-hydroxy acid (Fig. 8-6).

Fig. 8-6. Cerebrosides.

Globosides. Globosides differ from cerebrosides in that they contain multiple carbohydrate residues linked to a ceramide:

ceramide — glucose — galactose — galactose — N-acetylgalactosamine

Cerebrosides and globosides are classified as neutral sphingolipids because they do not contain charged groups.

Sulfatides. The hydroxyl group at the third carbon atom of the monosaccharide moiety in a cerebroside can bind a sulfuric acid residue, i.e., become sulfated. This produces sulfatides, which possess acidic properties and are therefore referred to as acidic sphingolipids (Fig. 8-7). At physiological pH values, the sulfated carbohydrate residue carries a negative charge. About 25% of brain cerebrosides are sulfated derivatives. Sulfatides are found in significant quantities in the White matter OF the brain.

Fig. 8-7. Sulfatides.

Gangliosides are the structurally most Complex Lipids. They contain multiple carbohydrate residues, among which N-acetylneuraminic acid is present. Neuraminic acid is a 9-carbon carbohydrate belonging to the group of sialic acids.

The STRUCTURE OF THE ganglioside Gm₂ can be represented by the following scheme:

Ganglioside nomenclature. Gangliosides are designated by the letter G, for example, G_m2. The subscript letters M, D, T, and Q indicate that the ganglioside molecule contains 1, 2, 3, or 4 sialic acid residues, respectively. The numerical subscript denotes a specific carbohydrate sequence within the ganglioside (Fig. 8-8).

Fig. 8-8. Ganglioside G_m2.

Gangliosides are found primarily in the ganglion cells of neural tissue, from which they derive their name. However, gangliosides are also present in the Plasma Membranes of many other cells, including erythrocytes, hepatocytes, Spleen cells, and other Organs. The primary role of gangliosides is determined by their involvement in intercellular contacts. Some gangliosides act as specific receptors for A number of Bacterial toxins.

B. Steroids

Steroids are derivatives of reduced condensed ring systems—cyclopentanoperhydrophenanthrenes.

In the human body, the principal steroid is cholesterol, and all Other Steroids are its derivatives. Plants, Fungi, and Yeasts do not synthesize cholesterol, but instead produce various phytosterols and mycosterols that are not assimilated by the human Organism. Bacteria are incapable of synthesizing steroids.

Cholesterol is a structural component of cell membranes, where it influences bilayer Organization by increasing membrane rigidity. It serves as a precursor for the synthesis of bile acids, steroid hormones, and vitamin D₃. Disrupted Cholesterol Metabolism leads to the development of atherosclerosis.

Cholesterol is a molecule containing four fused rings designated by the Latin letters A, B, C, and D, an 8-carbon branched side chain at position 17, two "angular" methyl groups (18 and 19), and a hydroxyl group at position 3. The presence of the hydroxyl group classifies cholesterol as an alcohol, making its correct chemical name "cholesterol", although the term "cholesterin" is still frequently used in medical literature.

The Esterification of fatty acids to the hydroxyl group via an ester bond yields cholesterol esters (Fig. 8-9).

Fig. 8-9. Cholesterol and its esters.

Unesterified cholesterol is an integral component of various cell membranes. The hydroxyl group of cholesterol faces the aqueous phase, whereas the rigid hydrophobic portion of the molecule is embedded within the inner hydrophobic core of the membrane (see Fig. 5-3).

In Blood Plasma, two-thirds of cholesterol circulates in an esterified form and one-third as free cholesterol. Cholesterol esters serve as a storage form of cholesterol in certain tissues (such as the liver, adrenal cortex, and Gonads). From these stores, cholesterol is mobilized for the synthesis of bile acids and steroid hormones.

Bile acids. Bile acids act as Surfactants and play a key role in lipid digestion by emulsifying dietary fats, thereby making them accessible to pancreatic lipase.

Bile acids are cholesterol derivatives featuring a five-carbon side chain at position 17 that terminates in a carboxyl group. Two primary bile acids are synthesized in the human body: cholic acid, which contains three hydroxyl groups at positions 3, 7, and 12 (Fig. 8-10), and chenodeoxycholic acid, which contains two hydroxyl groups at positions 3 and 7. Because the carboxyl groups of these bile acids have a pK of approximately 6, they are not fully dissociated at the physiological pH of the intestine and thus do not function as effective emulsifiers. In the liver, the emulsifying properties of bile acids are enhanced through conjugation, whereby taurine or Glycine—compounds fully ionized at intestinal pH—are attached to the carboxyl group of the bile acid. These derivatives, known as conjugated bile acids, exist in an ionized form and are referred to as bile salts. These are the principal agents responsible for lipid emulsification in the intestine.

Fig. 8-10. Bile acids.