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Lipid vesicles

Picture: “Lipid vesicles”by MDougM. License: Public Domain


Properties of Lipids

Lipids are either completely lipophilic and therefore completely apolar, or predominantly apolar. A lipid (or the lipid component of a compound) will dissolve in water either poorly or not at all. However, a lipid will dissolve in solvents such as alcohol and ether.

Grease drops on chicken bouillon is a good example of the non-solubility of fats in water. When fat is being digested (for example after eating chicken bouillon), mixed micelles spontaneously form within the digestive tract with the help of bile acid. Micelles are spherical aggregates. They are amphiphilic, meaning they are lipophilic inside while hydrophilic molecular components are found on the outside. During the spontaneous formation of micelles, all lipophilic components within the environment are included in these spherical aggregates. The micelles then migrate through the digestive tract and then passively enter mucosal cells where they are further transformed and transported to their destination.

Outside the body, lipids can bond with the help of detergents. Detergents are water-soluble organic substances that reduce surface tension and bind fat. Detergents can be found in dish soap.

Classification of Lipids

Lipids are a heterogeneous group and can be classified depending on the parameters considered.

Structural classification

A rough structural classification of lipids is based on distinguishing fatty acids (and their derivatives) from polyprenol compounds.

Fatty acids are divided into different categories, depending on the component they combine with. These different precursors are all combined with one or more fatty acids, including triglycerides, which constitute the structural fat within the human body, and sphingolipids, which are involved in the development of the nervous system.

Polyprenol compounds, on the other hand, do not contain fatty acids. Instead, they arise from the precursor, isoprene. Via folding and extension, they form useful substances such as fat-soluble vitamins, steroids (e.g., cholesterol), and terpenes which are present as menthol in cough sweets.

General chemical structure of sphingolipids.

Image: General chemical structure of sphingolipids. By: Karol Langner. License: Public Domain

Functional classification

Lipids can also be classified based on their function. It is possible to classify lipids according to the nature of their fatty acids and their chemical backbones. The main backbones are:

  • Glycerol
  • Sphingosine
  • Isoprene

Lipids with a glycerol backbone are part of the key component of the cell lipid bilayer. Additionally, they serve as key parts of intracellular and extracellular proteins and some second messengers.

Sphingosine-based lipids are also involved in the cell layer, but instead of being part of the signaling pathways, they are more readily recognized as part of the cell-to-cell recognition pathways. Moreover, there are many sphingosine-based lipids, such as ceramide, which are involved with apoptosis, autophagy, cell differentiation, and other processes.

Interestingly, the isoprene-based lipids form the base of many vitamins, including vitamins A, E, and K.

Classification according to reaction with water

Another classification method for lipids is based on their reactivity with water. This reaction is called hydrolysis, and the hydrolysis of fats is specifically referred to as alkaline hydrolysis. However, not all fats undergo alkaline hydrolysis. Non-hydrolyzable lipids include hydrocarbons (β-carotene), alcohols (cortisol), and acids (linoleic acid), while hydrolyzable lipids include certain (simple) esters (triglycerides in dietary fat, cholesterol), phospholipids (phosphatidylcholine), sphingolipids (e.g., membrane lipids of the nervous systems), and glycolipids (neural membrane lipids).

Fatty Acids

Regarding the chemistry of lipids, all lipids have a common structural element: activated acetic acid, i.e. acetyl-CoA. Acetyl -CoA is the central substance in lipid metabolism.

Lipid Metabolism

Image: Lipid metabolism. By: Phil Schatz. License: CC BY 4.0

Fatty acids are carbon chains of various lengths, with at least 4 carbon atoms. Up to 4 hydrogen atoms can be bound to the carbon atoms. At one end of the carbon chain is a methyl group, i.e., a carbon atom with 3 hydrogen atoms (CH3), and at the other end is an acidic carboxyl group (COOH), which is why the carbon chain is also called an acid.

Fatty acids are amphiphilic because they have a lipophilic end (carbon part) and a hydrophilic end (carboxyl group). The longer the carbon chain, the more the fatty acid acts in a lipophilic manner since the carbon part is responsible for the lipophilic properties. The opposite is true for short carbon chains, in which the hydrophilic properties dominate because of the influence of the hydrophilic carboxyl group.

Fatty acid degradation

Image: Fatty acid degradation. This chemical image was recreated using vector graphics. By: Jag123. License: Public Domain

Fatty acids can be found either separately or attached to other compounds. Fatty acids can be saturated or unsaturated. The most important building blocks of the human body with respect to esterification (i.e., the combining of fatty acids with another molecule) are glycerol (tertiary alcohol), isoprene (unsaturated hydrocarbon), and sphingosine (unsaturated amino alcohol).

Nomenclature of fatty acids

Fatty acids can be named in several ways. Firstly, they can be named according to the number of double bonds. Fatty acids without double bonds are regarded as saturated fatty acids; this means that 4 hydrogen atoms are bound to each carbon atom, hence, all binding sites are occupied (saturated) and the carbon atoms are bound by single bonds.

Two-dimensional representation of a saturated fatty acid

Image: Two-dimensional representation of a saturated fatty acid. By: Calvero. License: Public Domain

A monounsaturated fatty acid has 1 double bond between 2 carbon atoms at any point in the carbon chain, as not all binding sites are occupied by hydrogen atoms (unsaturated). Polyunsaturated fatty acids have at least 2 or more double bonds in the carbon tail.

The position of the double bond is important and is consequently noted in the name. It is possible to start counting from either side of the fatty acid; therefore, there are 2 ways of specifying the position of the double bond. If the counting starts from the carboxyl end, a delta (Δ) will be used, followed by a superscript number. The carbon atom of the carboxyl group is counted as 1 in this notation. Consequently, a fatty acid with Δ9 has its double bond between the 9th and 10th carbon atoms. (This could be, for example, the monounsaturated oleic acid with 18 carbon atoms and 1 double bond).

The configuration of the double bond may also be denoted as cis-Δ9-oleic acid. The “cis” means that the spatial arrangement of the double bond can be conceived as trapezoid. A trans configuration means that the double bond lies on the opposite side. All unsaturated fatty acids in the human body have a cis configuration.

Trans fats are well-known in the food industry. For these fatty acids, the double bond is configured differently compared to the ‘normal’ cis fatty acid. Such trans fatty acids are produced via the industrial hardening of vegetable fat—for example in the manufacture of margarine. Trans fatty acids have been incriminated as promoters of arteriosclerotic vascular alterations. Statutory regulations have now been established in many countries to reduce the amount of trans fats in food.

Apart from counting from the carboxyl end, the position of the double bond can also be determined by counting the carbon atoms from the other side. In this case, an omega (Ω) is written in front of the position of the double bond. This is the notation used for the well-known omega-3 and omega-6 fatty acids. Important examples of these fatty acids are:

  • Linoleic acid: Linoleic acid is an Ω-6 fatty acid (18:2 cis-Δ9,12; meaning 18 carbon atoms and 2 double bonds at positions 9 and 12 from the carboxyl end, or at position 6, counting from the methyl end).
  • Linolenic acid: Alpha-linolenic acid is an Ω-3 fatty acid (18:3 cis-Δ9,12,15; meaning 18 carbon atoms and 3 double bonds at positions 9, 12, and 15, counting from the carboxyl end, or at position 3 when counting from the methyl end).
  • Arachidonic acid: Arachidonic acid is also an Ω-6 fatty acid (20:4 cis-Δ5,8,11,14; meaning 20 carbon atoms and 4 double bonds at position 5, 8, 11, and 14, counting from the carboxyl end, or at position 6 counting from the methyl end).
arachidonic acid

Image: Arachidonic acid. By: NEUROtiker. License: Public Domain

Lastly, fatty acids can be specified in terms of whether the double bonds of the polyunsaturated fatty acid are isolated or conjugated. In humans, the double bonds of fatty acids are always isolated, which means that there are at least 2 single bonds between the double bonds. Conjugated double bonds are present if single and double bonds alternate with each other.

Significance of fatty acids

Fatty acids have several functions and are essential to the structure and function of the human body. They occur either by themselves, i.e. in isolated form (e.g. as transmitters such as eicosanoids which are synthesized from arachidonic acid) or in combination with other substances (e.g. together with glycerol as storage fat i.e. triglycerides).

One way the body obtains fatty acids is through food. Saturated fatty acids are mainly found in animal products, whereas plants often incorporate double bonds into their fatty acids, which means the human intake of unsaturated fatty acids is mainly via vegetable fats. The particularly valuable polyunsaturated fatty acids, which are commonly found in fish oil, are an exception. Essential fatty acids are found in vegetable oils, such as linseed oil, and in fish oil.

Long-chain fatty acids are crucial to the human body. Most fatty acids that are commonly eaten are relatively long. That means that they consist of at least 16 carbon atoms (e.g., palmitic acid). The human body can produce fatty acids from carbohydrates and can even insert double bonds, but this is not possible beyond carbon 9. However, since double bonds beyond carbon 9 are needed for specific functions, 3 specific fatty acids have to be supplied from an external source, namely the essential fatty acids linoleic acid and linolenic acid, and the semi-essential arachidonic acid.

linoleic acid

Image: Linoleic acid. By: Roland.chem. License: Public Domain

In impaired fat digestion, short-chain and medium-chain fats are used as dietary supplements. These fatty acids consist of only 4–12 carbon atoms and can be absorbed directly into the bloodstream without any input from pancreatic lipase. These medium-chain triglyceride fats are an important dietary supplement for patients with conditions like short bowel syndrome.

An important function of fatty acids is related to ‘local’ hormones — the eicosanoids. The eicosanoids are produced from arachidonic acid. They are either supplied via food or produced from linoleic or linolenic acid via elongation (elongation of the carbon chain) and desaturation (integration of a double bond).

Arachidonic acid (C:20:4, Ω-6 fatty acid) is produced from linoleic acid (C:18:2, Ω-6 fatty acid), and eicosapentaenoic acid (C:20:5, Ω-3 fatty acid) or docosahexaenoic acid (C:22:6, Ω-3 fatty acid) is formed from linolenic acid (C:18:3, Ω-3 fatty acid). These polyunsaturated fatty acids improve membrane fluidity. The eicosanoids — prostaglandin, thromboxane, and leukotriene — are formed from arachidonic acid (eicosatetraenoic acid). These substances are lipid mediators and act directly within the tissue in which they are released (hence the name ‘local’ hormones). They are involved in inflammatory responses, hemostasis, during the vasodilation of vascular capillaries, and in several other processes.

A lack of essential fatty acids can have severe consequences as it may result in membrane structure breakdown, leading to impaired intracellular metabolism. A lack of essential fatty acids may be evidenced by non-specific symptoms such as skin eczema, increased susceptibility to infection, or visual disturbances.

Storage Lipids

Properties of storage lipids

Fat is an excellent energy source (1 g provides 9 kcal of energy or 39 kJ per mol of energy), and fat can be stored very efficiently in terms of space as water is not essential to its storage (glycerol in the muscle also supplies energy but, since it is hydrophilic and is stored with water, this method of storing energy takes up very limited space). These properties mean that lipids are well-suited as energy stores, and this storage can be expanded almost indefinitely.

Esterification: how fats become energy stores

Triglycerides are commonly referred to as storage fat. Triglycerides, also called triacylglycerides or triacylglycerols, are categorized as glycolipids because the tertiary alcohol glycerol is esterified with 3 fatty acids. Thus, a triglyceride is a fatty acid ester. Various fatty acids can be esterified with glycerol. Palmitic acid (C:16:0) and stearic acid (C: 18:0) are usually found within storage fat.

The term ‘neutral fat’ includes triglycerides as the triglyceride molecules are uncharged, i.e. neutral. Triglycerides do not only act as food storage but can also be found in subcutaneous fat because of their strong insulating properties, and as structural fat owing to their protective properties. Examples of these may be seen in the orbital cavity (eye socket) or in the renal capsule.

Cholesterol esters

Via esterification, hydrophilic groups can be arranged in such a way that allows them to convert from being polar to neutral. This is how cholesterol is made transferable and storable. The cholesterol molecule is actually a very lipophilic molecule, which is why it can easily be stored as lipid droplets; however, it also possesses a hydroxyl group. This hydroxyl group is hydrophilic, meaning the above-mentioned form of storage is not possible. Esterification is the only method that facilitates the storage of cholesterol as cholesterol ester within the cell interior (cytosol) as it involves the cholesterol molecule being made nonpolar (neutral). The enzyme acyl-CoA-cholesterol acyltransferase performs this esterification within the cell interior.

Esterification also aids the transportation of this special molecule through the bloodstream. The amphiphilic structure of this molecule (which includes a large lipophilic part and a small hydrophilic part) specifically prevents micelle formation. This intermediate esterification, performed for the purpose of transport, is what allows cholesterol to be transported with the aid of lipoproteins (such as LDL). The esterification is performed by specific acyltransferases, which, as their name suggests, transfer an acyl group. The acyl group is a fatty acid, such as oleic acid or stearic acid. The acyltransferase present in the bloodstream and responsible for this task is lecithin-cholesterol acyltransferase. This enzyme uses lecithin for the esterification of a fatty acid.

Cholesterol has very diverse functions within the human body. It is an important membrane lipid and a starting substance for steroids. Steroid hormones regulate a variety of physiological functions. Important steroid hormones are the sex hormones, such as estrogen, progesterone, and testosterone, and the adrenal hormones aldosterone and cortisol.

From triglycerol to di(acyl)glycerol to mono(acyl)glycerol

Glycerol can be esterified with 3 fatty acids, although this does not have to occur. There are also variants with 2 fatty acids (diacylglycerol, DAG) or only 1 fatty acid (monoacylglycerol). During the formation of a triglycerol, an intermediate is formed (e.g. a diglycerol). DAG plays a significant role in transmitting signals to the membranes, in which case DAG is formed by a kinase from membrane-bound phosphatidylinositol. Monoacylglycerols are formed during the digestion of lipids by the action of lipases, with the goal of creating short lipophilic units for the formation of micelles.

Triglyceride Broken Down into a Monoglyceride

Image: Triglyceride broken down into a monoglyceride. By: Phil Schatz. License: CC BY 4.0

Membrane Lipids

Properties of membrane lipids

Apart from their storage function, one of the main functions of lipids is found within biological membranes which consist of lipids. The well-known lipid components of the membrane are glycerophosphatides, sphingosine phosphatides (which are located in the membranes of the CNS), and cholesterol.

As an intermediate product, lysoglycerophospholipid is formed. This molecule has a regulatory function as a signaling substance with respect to the neuronal membranes.

Schematic cross section of the lipid bilayer. The circles are the hydrophilic heads and the wavy lines are the fatty acyl side chains

Image: Schematic cross-section of the lipid bilayer. The circles are the hydrophilic heads and the wavy lines are the fatty acyl side chains. By: Masur. License: Public Domain

All membrane lipids have both hydrophobic and hydrophilic parts; thus, they are amphiphilic and this is a basic requirement in the function of the biological membrane. The biological membrane consists of a lipid bilayer.

In an aqueous environment, the membrane’s hydrophobic lipid tails are spontaneously oriented inwards and the hydrophilic lipid parts are oriented outwards; thus, the lipid bilayer is formed. This layer forms a natural barrier, isolating the compartments and the structures from each other. Proteins embedded into the membrane permit the transfer of a directed exchange of signals and of material, which can be regulated by lipid-head group reactions.

The spontaneous bilayer orientation of membrane lipids is employed in drug mechanisms. Apolar substances, such as certain drugs, can be transported through polar media in liposomes, which are vesicles whose shells resemble a cell membrane.

Structure of membrane lipids

Glycerophosphatides

As with triglyceride, the tertiary alcohol glycerol forms the backbone for the glycerophosphatides, but only 2 fatty acids are attached to the 3 possible binding sites, and a phosphate group is bound to the 3rd carbon atom of glycerol.

Yet another molecule is bound to this phosphate group. The bonds that are formed are called ester bonds. This is why this is also referred to as a phosphate diester bond because 2 ester bonds result, starting from the phosphatide (dissociated phosphatidic acid). Unlike triglyceride, the glycerophosphatide combines 2 contrasting features: the entire molecule has a nonpolar part (glycerol with 2 esterified fatty acids) and a polar part (the phosphate group with another polar binding partner).

Various polar groups can be esterified with the phosphatide group on the 3rd carbon atom of glycerol. A well-known example is the amino alcohol, choline, which involves the formation of phosphatidylcholine (better known as lecithin). Other glycerophosphatides are phosphatidylserine (serine is an amino acid), phosphatidylethanolamine (also known as cephalin; ethanolamine is an amino alcohol), and phosphatidylinositol (inositol is an amino alcohol). Another example of a glycerophosphatide is diphosphatidylglycerol, which is also known as cardiolipin and is found exclusively in the mitochondrial membrane.
.

Glycerophosphatides

Image: Glycerophosphatides. By: Lecturio

Sphingosine phosphatides

Sphingosine phosphatides are the main component of membranes that are located within the CNS. In these compounds, sphingosine, not glycerine, is the backbone to which fatty acids and phosphates are bound. Sphingosine is an amino alcohol that is present in the body, with a fatty acid attached to it (by an amide bond). This molecule is called ceramide. Numerous derivatives are based on ceramide such as sphingomyelin (a phospholipid) or the glycolipids – cerebroside and ganglioside.

Sphingolipids

Image: Membrane lipid metabolism – Sphingolipids. By: Lecturio

Sphingomyelin is located mainly in the myelin sheaths of the neurons. The hydroxyl group of ceramide is esterified with a phosphate group. An additional amino alcohol, choline, is bound to this phosphate group.

The cerebrosides are mainly found in the membranes of nerve cells and the substantia alba (white matter) of the brain; they also exist in the gangliosides in the brain and in the ganglia. Starting from ceramide, a carbohydrate group is bound to the hydroxyl group. If it is a monosaccharide (mostly galactose) then galactosylceramide is formed, which is also referred to as cerebroside. Occasionally, other molecules are bound to the hydroxyl group. Three to six complex carbohydrate groups can be bound to each other in gangliosides, one of which is the amino sugar N-acetylneuraminic acid.

Gangliosidosis, a hereditary disease, is the accumulation of gangliosides in the CNS, with the loss of affected cells. Severe developmental disorders result from gangliosidosis. Examples are Tay-Sachs disease and Niemann-Pick disease.

Cholesterol

Cholesterol has diverse functions in the human body, and as an amphiphilic molecule, it is also present in biological membranes. This characteristic is a result of its nonpolar ring system and its hydrophilic hydroxyl group. Cholesterol supports the construction of the lipid bilayer by embedding its rings between the fatty acids of the membrane lipids and by influencing fluidity. Optimal membrane fluidity is the basic requirement for maintaining membrane permeability and signal transmission.

Membrane-related means of communication

The hydrolysis of the membrane lipids results in the formation of second messengers, which are very important for signal transmission.

Inositol triphosphate (IP3) and DAG are formed from the membrane lipid phosphatidylinositol. Phosphatidylinositol-4,5-bisphosphate (PIP2) is formed by double phosphorylation. Thereafter, IP3 and DAG can be formed by the hydrolysis of PIP2. Both molecules are involved in signal transduction cascades: DAG activates protein kinase C, and IP3 stimulates the intracellular release of calcium.

Reactions with Reactive Oxygen Species

Just as butter becomes rancid when it reacts with oxygen, free oxygen radicals in the membrane lipids can also cause a reaction. Free radicals are formed as a byproduct of many reactions in the organism, such as mitochondrial ATP production in the respiratory chain. If there are esterified (poly)unsaturated fatty acids in the membrane, then lipid peroxidation, a reaction with free radicals, may easily occur. This creates fatty acid radicals which are very reactive and will react with fatty acids within the environment. This may lead to profound structural changes in the membrane and cause inflammation.

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