Table of Contents
Properties of Lipids
Lipids are either completely lipophilic and therefore apolar, or they possess a greater apolar proportion. A lipid (or the lipid component) will dissolve in water either poorly or hardly at all, but it will dissolve in solvents such as alcohol and ether.
Grease drops sitting on top of chicken bouillon would be a well-known example of the non-solubility of fats in water. When fat is being digested (for example after eating the chicken bouillon in question), mixed micelles form spontaneously within the digestive tract, with the help of bile acid. Micelles are spherical aggregates. They are amphiphilic, which means that the inside is lipophilic and hydrophilic molecular components are found on the outside. During the spontaneous formation of micelles, all lipophilic components within the environment are included into these spherical aggregates. After that, the micelles migrate through the digestive tract for a while, and then passively enter the mucosal cell where they are further transformed ahead of onward transportation to their destination.
Outside the body, lipids can bond with the help of detergents. These water-soluble organic substances reduce the surface tension, which binds the fat. Detergents can be found for example in dish soap.
The Classification of Lipids
In attempting to classify lipids—which constitutes a very heterogeneous group—they will be classified differently, depending on which author you take into consideration and which aspects underlie that classification.
The rough structural classification of lipids has been formulated by distinguishing fatty acids (and their derivatives) from polyprenol compounds.
Fatty acids are placed into different categories, depending on which component they combine with. These different precursors are all combined with one or more fatty acids. These fatty acids include, for example, the triglycerides, which constitute the structural fat within the human body, and the sphingolipids, which are involved in the development of the nervous system.
Polyprenol compounds, on the other hand, manage without fatty acids. Instead, they arise from the precursor isoprene. By the mechanisms of folding and extension, they form useful substances—such as fat-soluble vitamins, steroids such as cholesterol, and also terpenes, which we are familiar with in the form of the menthol in cough sweets.
Another way of classifying lipids is based more on functional aspects. It is possible to divide the lipids according to the nature of their fatty acids and the nature of their backbones. The main backbones are:
Classification According to the Reaction with Water
Another variation in the classification of 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. But this is not possible with every kind of fat, thus non-hydrolysable lipids include hydrocarbons (β-carotene), alcohols (cortisol), and acids (linoleic acid). However, those that are hydrolysable include certain (simple) esters (triglycerides in dietary fat, cholesterol), phospholipids (phosphatidylcholine) and sphingolipids (for example, membrane lipids of the nervous systems), and glycolipids (neural membrane lipids).
When dealing with the chemistry of lipids, fatty acids are worth a closer look since all lipids have, as mentioned above, a common structural element: activated acetic acid, i.e. acetyl-CoA. Acetyl -CoA is the central substance in lipid metabolism, without which nothing would work.
Fatty acids are carbon chains of various lengths, with at least four carbon atoms. Up to four 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 three 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 both a lipophilic end (the carbon part) and a hydrophilic end (the carboxyl group). The longer the carbon chain, the more the fatty acid acts lipophilically since the carbon part is responsible for the lipophilic properties. The opposite is true for short carbon chains, in which hydrophilic properties dominate, due to the fact that the influence of the hydrophilic carboxyl group is brought to bear.
Fatty acids can be found either separately, in individual form, or they are attached to another compound. Fatty acids can be saturated or unsaturated. The most important building blocks for the human organism with respect to esterification (i.e., the combining of fatty acids with another molecule) are glycerol (a tertiary alcohol), isoprene (an unsaturated hydrocarbon), and sphingosine (an unsaturated amino alcohol).
The Nomenclature of Fatty Acids
There are many varieties of nomenclature when it comes to fatty acids. It firstly depends on the number of double bonds. If there is no double bond, then we are dealing with a saturated fatty acid; this means that there are four hydrogen atoms bound to each carbon atom, hence, all binding sites are occupied (saturated) and the carbon atoms are bound by single bonds.
A monounsaturated fatty acid has one double bond between two 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 two or more double bonds in the carbon tail.
The position of the double bond is of importance and is consequently also given in the name. It is, of course, possible to start counting from either side of the fatty acid, and there are therefore two ways of specifying the position of the double bond. If 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 atom. (This could be, for example, the monounsaturated oleic acid with 18 carbon atoms and one double bond).
But that is not all: the configuration of the double bond may also be given: cis-Δ9-oleic acid. The “cis” means that the spatial arrangement of the double bond can be conceived as trapezoid. Trans configuration means that the double bond lies on the opposite side. All unsaturated fatty acids in the human organism have a cis configuration.
Various so-called trans fats are well-known from the food industry. These fatty acids are characterized by the fact that their double bond is configured differently, compared to the “normal” cis fatty acid. Such trans-fatty acids are produced via technological hardening of vegetable fat—for example in the manufacture of margarine. Trans-fatty acids have been discredited as promoting arteriosclerotic vascular alterations. Statutory regulations have now been established in many countries to reduce the amount of trans fats in food.
Besides 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 three 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 four double bonds at position 5,8,11, and 14 counting from the carboxyl end, or at position 6 counting from the methyl end).
Lastly, the fatty acids can be specified in terms of whether the double bonds of the polyunsaturated fatty acid are isolated or conjugated. Within the human organism, the double bonds of the fatty acids are always isolated, which means that there are at least two single bonds between the double bonds. Conjugated double bonds are present if single and double bonds alternate with each another.
The Significance of Fatty Acids
Fatty acids have multiple functions and are essential to the structure and function of the human body. They occur either by themselves, i.e. in isolated form—for example as transmitters such as eicosanoids (which are synthesized from arachidonic acid)—or in combination with other substances—for example, together with glycerol as storage fat (triglycerides).
One way of getting fatty acids into the body is through food. Saturated fatty acids are mainly found in animal products, whereas plants often incorporate double bonds into their fatty acids, which mean 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, for example.
Long-chain fatty acids are of most relevance 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 on its own, and can even insert double bonds, but this is only possible as far as carbon 9. However, since double bonds beyond carbon 9 are needed for specific functions, three 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.
In the particular case of impaired fat digestion, short- and medium-chain fats are used in the diet. These fatty acids consist of only four to 12 carbon atoms and they can be absorbed directly into the bloodstream without any input from pancreatic lipase. These so-called MCT fats can provide an important dietary supplement for patients with, e.g., short bowel syndrome.
But why does the body actually need these fatty acids? An important function of fatty acids relates to so-called “local” hormones, the eicosanoids. These are produced from arachidonic acid. They are either supplied via food intake or produced from the essential linoleic acid or from 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-6fatty acid); and eicosapentaenoic acid (C:20:5, Ω-3 fatty acid) or docosahexaenoic acid (C:22:6, Ω-3 fatty acid) are 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 the so-called lipid mediators and they act directly within the tissue in which they are released (hence the name “local” hormones). They are involved in inflammatory responses, hemostasis, and the vasodilation of vascular capillaries, for example, along with numerous other processes—which will be described in detail in the corresponding chapter.
A lack of essential fatty acids can have severe consequences as this may result in a breakdown in the structure of the membrane, leading to a breakdown in intracellular metabolism. A lack of essential fatty acids may be evidenced by non-specific symptoms such as skin eczema and increased susceptibility to infection, or visual disturbances.
The Properties of Storage Lipids
Fat is an excellent energy source (1 gram provides 9 kcal of energy, or 39 kJ per mol), and fat can be stored very efficiently in terms of space because it can manage without water (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 to act as an energy store for times of need and, as you may have noticed, this storage can be expanded almost indefinitely.
Esterification: How Fat Becomes Storage
Triglycerides are commonly referred to as storage fat. Triglycerides, sometimes also called tiracylglycerides or triacylglycerols, are categorized as glycolipids, as the tertiary alcohol glycerol is esterified with three fatty acids. A triglyceride is, therefore, 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. You may sometimes come across the term ‘neutral fat’. The term ‘neutral fat’ also includes triglycerides as these molecules are uncharged, i.e. neutral. Triglycerides do not only serve the purpose of food storage—they can also be found in subcutaneous fat, thanks to their strong insulating properties, and as structural fat, thanks to their protective properties, for example in the orbital cavity (the eye socket) or in the renal capsule.
By means of esterification, hydrophilic groups can be packaged in such a way that it allows them to be converted from being polar to being neutral. This is how cholesterol is made transferable and storable. The cholesterol molecule is actually a very lipophilic molecule, which is why it could easily be stored as lipid droplets; however, it also possesses a hydroxyl group (OH Group). This OH group is hydrophilic, meaning the above-mentioned form of storage is not possible. Esterification is the only thing that facilitates the storage of cholesterol as cholesterol ester within the cell interior (cytosol) as it involves the cholesterol molecule being made nonpolar (neutral). It is the enzyme acyl-CoA-cholesterol acyltransferase that performs the esterification within the cell interior.
Esterification also aids transportation of this special molecule through the bloodstream. The amphiphilic structure of this molecule (which includes both a large lipophilic part and a small hydrophilic part) specifically prevents micelle formation. It is only thanks to the intermediate esterification, performed for the purpose of transport, that the cholesterol can 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 (LCAT). This enzyme uses lecithin for the esterification of a fatty acid.
Cholesterol is responsible for very diverse functions within the organism. 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 three fatty acids, although this does not have to occur. There are also the variants which have two fatty acids (diacylglycerol, DAG) or only one fatty acid (monoacylgycerol). When building a triglycerol, an intermediate is formed—for example a diglycerol. Diacylglycerol plays a significant role in transmitting signals to the membranes. In this case, the DAG is formed by a kinase from membrane-bound phosphatidylinositol. Monoacylyceroles 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.
The Properties of Membrane Lipids
Besides their storage function, one of the main purposes of lipids is found within the membranes of the organism. Every biological membrane consists of lipids. The well-known components are: glycerophosphatides, sphingosinphosphatides (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 signalling substance with respect to the neuronal membranes.
All membrane lipids have both hydrophobic and hydrophilic parts. This two-faced property is called amphiphilic and it is a basic requirement for constructing a 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, whereby 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 put to use in drugs, for example. Apolar substances, such as certain drugs, can be transported through polar media in so-called liposomes, which are vesicles whose shell is similar to a cell membrane.
The Structure of Membrane Lipids
As with triglyceride, the tertiary alcohol glycerol forms the backbone for the glycerophosphatides, but there are only two fatty acids attached to the three possible binding sites, and a phosphate group is bound to the third 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 it is also referred to as a phosphate diester – as two ester bonds result, starting from the phosphatide (dissociated phosphatide acid). In contrast to triglyceride, the glycerophosphatide combines two contrasting features: the entire molecule has both a nonpolar part (glycerol with two esterified fatty acids) and a polar part (the phosphate group with another polar binding partner).
There are various polar groups which can be esterified with the phosphatide group on the glycerol’s third carbon atom. A well-known example is the aminoalcohol 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.
The sphingosinphosphatides are the main component of membranes that are located within the central nervous system. It is not glycerine that forms the backbone in this case, but sphingosine to which fatty acids and phosphates are bound. Sphingosine is an amino alcohol which is always 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.
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; 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—in most cases, it is galactose —then galactosylceramide is formed, which is also referred to as cerebroside. Sometimes, other things are bound to the OH group. Three to six complex carbohydrate groups are can be connected 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 and loss of the affected cells. Severe developmental disorders result. Examples are Tay-Sachs disease and Niemann-Pick disease.
Cholesterol is a real multiplayer in the human body, and as an amphiphilic molecule, it also is present in the 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 the maintenance of functioning membrane permeability and signal transmission.
Membrane-Related Means of Communication
Hydrolysis of the membrane lipids results in the formation of second messengers, which are very important for signal transmission:
Inositol triphosphate (IP3) and diacylglycerol (DAG) are formed from the membrane lipid phosphatidylinositol. Phosphatidylinositol-4,5-bisphosphate—PIP2 in short—is formed by double phosphorylation. Then, IP3 and DAG can be formed by hydrolysis of PIP2. Both molecules are involved in signal transduction cascades: DAG activates the 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, for example. If there are esterified (poly)unsaturated fatty acids in the membrane lipids, then lipid peroxidation, a reaction with free oxygen radicals, may easily occur. This creates a fatty acid radical which is very reactive and will react with the fatty acids within the environment. This may lead to profound structural changes in the membrane and cause inflammation.
Popular Exam Questions on Lipids
Solutions can be found below the references.
1. Liposomes may be used therapeutically as a carrier for pharmaceutical substances. Which statement best describes a liposome?
- If it has a diameter of at least 100 nm, it is considered a micelle.
- It has a shell made out of a lipid monolayer.
- It has a shell made out of one or more lipid bilayers.
- It is lipolytically active.
- There is a lipid phase in the center of the liposome.
- …contains three hydroxyl groups.
- …contains two proteinogenic amino acids.
- …is a component in a ceramide.
- …is a component in a glycerolipid.
- …is a thioether.
3. The human body can synthesize arachidonic acid from which fatty acid?
- Butanoic acid
- Ethanoic acid
- Linoleic acid
- Oleic acid
- Stearic acid
Horn, Florian: Biochemie des Menschen. 5. Auflage. Georg Thieme Verlag. Stuttgart. 2012
Duale Reihe: Biochemie. 2. Auflage. Georg-Thieme-Verlag. Stuttgart. 2008
Schwarze Reihe: 1. ÄP. Biochemie. 19. Auflage. Georg-Thieme-Verlag. Stuttgart. 2008
Biesalski, Hans Konrad: Taschenatlas der Ernährung. 2. Auflage. Georg-Thieme-Verlag. Stuttgart. 2002
Correct answers: 1C, 2C, 3C