Lipids: An Overview

Lipids: An Overview

• Lipids are a diverse group of compounds.
• Lipids include:
  • Fats
  • Oils
  • Steroids
  • Waxes
  • Related compounds
• Lipids are primarily related by physical properties rather than chemical properties.
• Lipids are relatively insoluble in water, but soluble in nonpolar solvents like:
  • Ether
  • Chloroform

Functions of Lipids

• Lipids serve as a storage form of energy.
• Lipids are dietary components because of:
  • High energy value
  • Fat-soluble vitamins
  • Essential fatty acids
• Lipids are structural components of biomembranes.
• Lipids act as thermal insulators:
  • Subcutaneous tissues
  • Around certain organs
• Nonpolar lipids act as electrical insulators, enabling rapid nerve depolarization.
• Lipids provide shape and contour to the body.
• Lipids act as metabolic regulators.
• Lipoproteins, combinations of lipid and protein, are:
  • Important cellular constituents
  • Found in cell membranes and mitochondria
  • Transport lipids in the blood

Clinical Significance

• Diseases associated with abnormal lipid chemistry or metabolism:
  • Obesity
  • Atherosclerosis
  • Diabetes Mellitus
  • Hyperlipoproteinemia
  • Fatty liver
  • Lipid storage diseases

Classification of Lipids

• Simple lipids are esters of fatty acids with various alcohols.
• Fats are esters of fatty acids with glycerol.
• Oils are fats in the liquid state.
• Waxes are esters of fatty acids with higher molecular weight monohydric alcohols.
• Complex lipids are esters of fatty acids, alcohols, and additional groups.
• Phospholipids contain fatty acids, an alcohol, and a phosphoric acid residue; nitrogenous bases and other substituents are frequently present.
  • Glycerophospholipids contain glycerol.
  • Sphingophospholipids contain sphingosine.
• Glycolipids (glycosphingolipids) contain a fatty acid, sphingosine, and a carbohydrate.
• Sulfolipids and aminolipids are other complex lipids.
• Lipoproteins can also be classified as complex lipids.
• Precursor and derived lipids include:
  • Fatty acids
  • Glycerol
  • Steroids
  • Other alcohols
  • Fatty aldehydes
  • Ketone bodies
  • Hydrocarbons
  • Lipid-soluble vitamins
  • Hormones

Fatty Acids

• Fatty acids are aliphatic carboxylic acids.
• General formula: R-(CH2)n-COOH
• Fatty acids occur mainly as esters in natural fats and oils.
• Fatty acids occur in the unesterified form as free fatty acids in the plasma.
• Fatty acids in natural fats are usually straight-chain derivatives with an even number of carbon atoms.
• Chains may be saturated (no double bonds) or unsaturated (one or more double bonds).

Classification of Fatty Acids

• Fatty acids are classified by:
  • Nature of the hydrophobic chain
    • Saturated
    • Unsaturated
    • Branched-chain
    • Substituted
• Saturated fatty acids lack double bonds.
• Unsaturated fatty acids contain double bonds.

Saturated Fatty Acids

• Saturated fatty acids can be regarded as derivatives of acetic acid (CH3–COOH).
• Biological systems contain saturated fatty acids with even numbers of carbon atoms, typically between 14 and 24.
• The 16- and 18-carbon fatty acids are common.
• Animal fatty acid hydrocarbon chains are almost invariably unbranched.
• Branched-chain fatty acids can also be found in plant and animal sources.
• Acetic acid has 2 carbon atoms with the formula CH3COOH.
• Butyric acid has 4 carbon atoms with the formula CH3(CH2)2COOH.
• Caproic acid has 6 carbon atoms with the formula CH3(CH2)4COOH.
• Caprylic acid has 8 carbon atoms with the formula CH3(CH2)6COOH.
• Capric acid has 10 carbon atoms with the formula CH3(CH2)8COOH.
• Lauric acid has 12 carbon atoms with the formula CH3(CH2)10COOH.
• Myristic acid has 14 carbon atoms with the formula CH3(CH2)12COOH.
• Palmitic acid has 16 carbon atoms with the formula CH3(CH2)14COOH.
• Stearic acid has 18 carbon atoms with the formula CH3(CH2)16COOH.
• Arachidic acid has 20 carbon atoms with the formula CH3(CH2)18COOH.
• Behenic acid has 22 carbon atoms with the formula CH3(CH2)20COOH.

Unsaturated Fatty Acids

• Monounsaturated acids contain one double bond.
• Polyunsaturated acids contain two or more double bonds.
• The configuration of double bonds in unsaturated fatty acids is typically cis.
• Double bonds in polyunsaturated fatty acids are separated by at least one methylene group.

Nomenclature of Fatty Acids

• Oic is substituted to the name of the parent hydrocarbon's systematic name to derive the systematic fatty acid name.
• Octadecanoic acid is the name for the C18 saturated fatty acid because the parent hydrocarbon is octadecane.
• A C18 fatty acid with one double bond is octadecenoic acid.
• A C18 fatty acid with two double bonds is octadecadienoic acid.
• A C18 fatty acid with three double bonds is octadecatrienoic acid.
• The notation 18:0 denotes a C18 fatty acid with no double bonds.
• The notation 18:2 signifies that there are two double bonds.
• Carbon atoms are numbered from the carboxyl carbon (carbon No. 1).
• Carbons 2, 3, and 4 are known as the α, β, and γ carbons, respectively.
• The terminal methyl carbon is known as the ω or n-carbon.
• The position of a double bond is represented by the symbol Δ followed by a superscript number.
• Δ9 indicates a double bond between carbons 9 and 10 of the fatty acid.
• The position of a double bond can be denoted by counting from the distal end, with the ω-carbon atom as number 1.
• ω9 indicates a double bond on the ninth carbon counting from the ω-carbon.
• In animals, additional double bonds are introduced between the existing double bond and the carboxyl carbon.
• Three series of fatty acids are known as the ω9, ω6, and ω3 families.

Cis and Trans-Isomers

• Depending on the orientation of the radicals around the axis of the double bond:
  • Cis: Radicals are on the same side.
  • Trans: Radicals are on the opposite side.
• Oleic acid and Elaidic acid have the same formula.
  • Oleic acid is cis.
  • Elaidic acid is trans.
• Saturated fatty acid hydrocarbon chains are straight and pack closely, making fats solid at room temperature.
• Oils, mostly from plant sources, have some double bonds in the hydrocarbon tail, causing bends or "kinks".
• An increase in cis double bonds leads to a variety of spatial configurations.
  -Arachidonic acid, with four cis double bonds, has "kinks".
• The kinks impact the tails and the pack, making them liquid at room temperature.
• Higher temperatures cause rotation, which explains why biomembranes become thinner.

Trans Fatty Acids

• Trans fatty acids are by-products of the hydrogenation of natural oils in margarine manufacture.
• Ruminant fat contains trans fatty acids arising from microorganism action.
• Unsaturated vegetable oils have almost all cis bonds. Frying oil converts some cis bonds to trans bonds.

Fatty Chains

• Phytanic acid is present in butter.
• Sebum also contains branched chain fatty acids.
• There may be even or odd chain fatty acids.
• Even chain fatty acids are predominantly present.
• Cyclic fatty acids include Chaulmoogric acid and Hydnocarpic acid.
• Cerebronic acid is a substituted fatty acid, specifically an OH fatty acid.

Classification by Length

• Classified by length:
  • Short chain: 2-6 carbon atoms
  • Medium chain: 8-14 carbon atoms
  • Long chain: 16-18 carbon atoms
  • Very long chain: 20 or more carbon atoms

Biological Importance

• Fatty acids are building blocks of dietary fats.
• The human body stores fats as triglycerides.
• Fatty acids are needed for membrane lipids (phospholipids and glycolipids).
• They are required for esterification of cholesterol to form cholesteryl esters.
• They act as fuel molecules and are oxidized to produce energy.

Essential Fatty Acids

• Polyunsaturated fatty acids (Linoleic and Linolenic acids) are essential for life functions.
• Arachidonic acid is considered a semi-essential fatty acid since it can be synthesized from Linoleic acid.
• Essential polyunsaturated fatty acids are classified into omega-6 and omega-3 families.
• Fatty acids in these families differ in chemistry, occurrence, and biological functions.
• Significance of essential fatty acids:
  • Components of cell membranes
  • Structural elements of gonads and mitochondrial membrane
  • Required for brain growth and development
  • Precursors of Eicosanoids
  • Important role in vision
  • Cardio-protective role (lower serum cholesterol and increase HDL)
  • Prevent fatty liver formation
• Deficiencies in essential polyunsaturated fatty acids may cause various symptoms.

Glycerol

• Glycerol is also called 'Glycerin'.
• Glycerol is a trihydric alcohol with three hydroxyl groups.
• It can be obtained from:
  • Diet
  • Lipolysis of fats in adipose tissue
  • Glycolysis
• It can be utilized in:
  • Synthesis of triacylglycerols, phospholipids, glucose
  • Oxidation to provide energy
• Glycerol is used as a solvent in drugs and cosmetics.
• Nitroglycerine is used as a vasodilator.
• The -sn (stereochemical numbering) system is used to number carbon atoms of glycerol unambiguously.
• Carbons 1 and 3 of glycerol are not identical when viewed in three dimensions.
• Enzymes can distinguish between them.
• Glycerol is phosphorylated on sn-3 by glycerol kinase to give glycerol 3-phosphate, but not glycerol 1-phosphate.

Cholesterol

• Cholesterol is the most important sterol in the human body, with molecular formula C27H45OH.
• Cholesterol possesses a cyclopentanoperhydrophenanthrene ring nucleus.
• Structural features of Cholesterol:
  • An -OH group at C3
  • A double bond between C5 and C6
  • Two -CH3 groups at C10 and C13
  • An eight-carbon side chain attached to C17

Forms

• Cholesterol occurs as both a free form or in ester form.
• In cholesteryl ester, the hydroxyl group on position 3 is esterified with a long-chain fatty acid.
• Cholesterol esters are formed by acyltransferases (LCAT and ACAT).
• In plasma, both forms are transported in lipoproteins.
• Plasma low-density lipoprotein (LDL) is the vehicle of uptake of cholesterol and cholesteryl ester into many tissues.
• Free cholesterol is removed from tissues by plasma high-density lipoprotein (HDL) and transported to the liver, where it is eliminated either unchanged or after conversion to bile acids in a process referred to as reverse cholesterol transport.
• The sum total of cholesterol in serum is called serum total cholesterol.

Significance

• Cholesterol is widely distributed in all cells but particularly in nervous tissue.
• It is a major constituent of plasma membranes and plasma lipoproteins.
• It is synthesized in many tissues from acetyl-CoA.
• Cholesterol is the precursor of other steroids in the body, including:
  • Corticosteroids
  • Sex hormones
  • Bile acids
  • Vitamin D
• Cholesterol is a major constituent of gallstones.
• The primary role in pathologic processes is in atherosclerosis of vital arteries.

Normal Serum Level

• Normal level of serum total cholesterol ranges between 150-220 mg/dL.

Physiological variations:

• Low at birth.
• Increases with age.
• Increased during pregnancy.

Pathological variations:

• Low cholesterol (Hypocholesterolemia):
  • Thyrotoxicosis
  • Anemia
  • Hemolytic jaundice
  • Wasting diseases
  • Malabsorption syndrome
• Hypercholesterolemia:
  • Nephrotic syndrome
  • Diabetes Mellitus
  • Obstructive Jaundice
  • Myxoedema
  • Xanthomatous biliary cirrhosis
  • Hypopituitarism
  • Familial Hypercholesterolemia
  • Idiopathic

Other Sterols

• 7-dehydrocholesterol- Also known as Provitamin D3 (Precursor of vitamin D)
• Ergo sterol-plant sterol (First isolated from Ergot- Fungus of Rye)
• Stigmasterol and Sitosterol- Plant sterols
• Coprosterol (Coprostanol)- Reduced products of cholesterol- found in feces

Classed as other steroids are:

• Bile acids
• Adrenocortical hormones
• Gonadal hormones
• D vitamins
• Cardiac glycosides.

Simple Lipids

• Neutral fats or Triacyl Glycerides are esters of the trihydric alcohol, glycerol and fatty acids.
• Mono- and Diacylglycerol, wherein one or two fatty acids are esterified with glycerol, are also found in the tissues.
• Naturally occurring fats and oils are mixtures of triglycerides.
• If all the OH groups are esterified to same fatty acids- It is Simple Triglyceride
• If different fatty acids are esterified- It is known as Mixed triglyceride.
• Polyunsaturated fatty acid is esterified at 2nd position.
• Properties of triglycerides:
  • Colourless, odourless and tasteless.
  • Insoluble in water.
  • Specific gravity is less than 1.0.
  • Consequently, all fats float in water.
  • Oils are liquids at 20°C, and they contain higher proportion of Unsaturated fatty acids.
  • Fats are solid at room temperature and contain saturated long chain fatty acids.
• Triglycerides are the storage form of energy in adipose tissue.
• Triglycerides in the body are hydrolyzed by Lipases.

Lipases

• Lipases are enzymes which catalyze the hydrolysis of triglycerides yielding fatty acids and glycerol.
• Lipases are present in:
  • Lingual Lipase-In saliva
  • Gastric lipase- in gastric juice.
  • Pancreatic lipase-in pancreatic juice.
  • Intestinal lipase- in intestinal epithelial cells.
  • Hormone sensitive lipase - in adipose tissue.

Properties of Triglycerides

• Saponification occurs when the triglycerides are hydrolyzed by alkali.
• Fats and oils are have a tendency to become rancid.
• Rancidity refers to the appearance of unpleasant taste and smell of fats.
• Hydrolytic rancidity is due to partial hydrolysis of triglycerides due to traces of lipases.
• Oxidative rancidity is due to partial oxidation of unsaturated fatty acids with the resultant formation of epoxides and peroxides by free radicals.

Waxes

• Waxes are esters of higher fatty acids with higher mono hydroxy aliphatic alcohols(e.g. Cetyl alcohol).
• Have very long straight chain of 60–100 carbon atoms.
• It can take up water without getting dissolved in it.
• Used as bases for the preparation of:
  • Cosmetics
  • Ointments
  • Polishes
  • Lubricants
  • Candles
• Found on the surface of plants and insects

Phospholipids

• This class of lipid contains in addition to fatty acids and glycerol/or other alcohol, a phosphoric acid residue, nitrogen containing base and other substituents.
• Phospholipids may be regarded as derivatives of phosphatidic acid , in which the phosphate is esterified with the —OH of a suitable alcohol.
• They are amphipathic molecules containing a polar head and a hydrophobic portion.
• Classification of phospholipids:
  • Based on nature of alcohol
• Glycerophospholipids- Glycerol is the alcohol group

Examples of Glycerophospholipids:

• Phosphatidyl choline
• Phosphatidyl ethanolamine
• Phosphatidyl serine
• Phosphatidyl inositol
• Phosphatidic acid
• Cardiolipin
• Plasmalogen
• Platelet activating factor
• Phosphatidyl Glycerol
• Sphingophospholipids- Sphingol is the alcohol group.
  • Example- Sphingomyelin

Glycerophospholipids

• Phosphatidylcholines (Lecithins)
  • Phosphoacylglycerols containing choline are the most abundant phospholipids of the cell membrane.
  • Are present a large proportion of the body's store of choline.
  • Choline is important in nervous transmission, as acetylcholine, and as a store of labile methyl groups.
  • Dipalmitoyl lecithin is a very effective surface- active agent and a major constituent of the surfactant preventing adherence, due to surface tension, of the Inner surfaces of the lungs. Its absence from the lungs of premature infants causes respiratory distress syndrome.
• Phosphatidyl ethanolamine (cephalin)-
  • Structurally similar to Lecithin with the exceptions -That the base Ethanolamine replaces choline. -Brain and nervous tissue are rich in Cephalin
• Phosphatidyl Serine-(found in most tissues) differ from phosphatidylcholine only in that serine replaces choline.
• Phosphatidylinositol -The inositol is present in phosphatidylinositol as the stereoisomer, myoinositol.
  • Phosphatidylinositol 4,5-bisphosphate is an important constituent of cell membrane phospholipids;
  • upon stimulation by a suitable hormone agonist, it is cleaved into diacylglycerol and inositol trisphosphate, both of which act as internal signals or second messengers.
• Cardiolipin - - Abundantly found in mitochondrial membrane. -This is the only phospholipid with antigenic properties.
• Plasmalogens -
  • constitute as much as 10% of the phospholipids of brain and muscle.
  • Structurally, the plasmalogens resemble phosphatidylethanolamine but possess an ether link on the sn-1 carbon instead of the ester link found in acylglycerols.
  • Typically, the alkyl radical is an unsaturated alcohol.
  • In some instances, choline, serine, or inositol may be substituted for ethanolamine.
• Platelet activating factor (PAF)-
  • Ether glycerophospholipid.
  • Contains an unsaturated alkyl group in an ether link to carbon -1.
  • An acetyl residue at carbon 2 of the glycerol backbone.
  • Synthesized and released by various cell types.
  • PAF activates inflammatory cells and mediates hypersensitivity, acute inflammatory and anaphylactic reactions.
  • Causes platelets to aggregate and degranulate and neutrophils and alveolar macrophages to generate superoxide radicals.
• Phosphatidyl Glycerol- - Formed by esterification of phosphatidic acid with glycerol. - Diphosphatidyl glycerol, cardiolipin is found in the mitochondrial membrane.

Sphingophospholipids

• Sphingomyelin-
• Backbone is sphingosine (amino alcohol).
• A long chain fatty acid is attached to amino group of sphingosine to form Ceramide.
• The alcohol group at carbon- 1 of sphingosine is esterified to phosphoryl choline, producing sphingomyelin.
• Sphingomyelin is an important component of myelin of nerve fibers.

Functions of Phospholipids

• Components of cell membrane, mitochondrial membrane and lipoproteins.
• Participate in lipid absorption and transportation from intestine.
• Play important role in blood coagulation.
• Required for enzyme action- especially in mitochondrial electron transport chain.
• Choline acts as a lipotropic agent.
• Membrane phospholipids acts as source of Arachidonic acid.
• Act as reservoir of second messenger- Phosphatidyl Inositol.
• Act as cofactor for the activity of Lipoprotein lipase.
• Phospholipids of myelin sheath provide insulation around the nerve fobers.
• Dipalmitoyl lecithin acts as a surfactant.

Lecithin/Sphingomyelin Ratio

• LS Ratio in amniotic fluid is used for the evaluation of fetal lung maturity
• Prior to 34 weeks gestation, lecithin and sphingomyelin concentrations are equal but afterwards there is marked increase in Lecithin concentration.
• A LS ratio of> 2 or > 5 indicates adequate fetal lung maturity
• Delivery of a premature, low birth weight baby with low LS ratio (1 or<1) predisposes the child to respiratory distress syndrome.

Glycolipids

• Glycolipids differ from sphingomyelins in that they do not contain phosphoric acid and the polar head function is provided by monosaccharide'or oligosaccharide attached directly to ceramide by an O- glycosidic linkage.
• The number and type of carbohydrate moieties present, determine the type of glycosphingolipid.

There are two types of Glycolipids:

• Neutral glycosphingolipids
• Acidic glycosphingolipids

Neutral Glycosphingolipids

• Cerebrosides- These are ceramide monosaccharides, that contain either a molecule of galactose (Galactocerebroside)or glucose(Glucocerebroside).
• Found predominantly in the brain and nervous tissue with high concentration in myelin sheath.
• Ceramide oligosaccharides (Globosides) are produced by attaching additional monosaccharides to Glucocerebroside.
• Lactosyl ceramide contains lactose (Galactose and Glucose attached to ceramide).
• Cerebrosides (Contd.) Individual cerebrosides are differentiated on the basis of kind of fatty acids in the molecule.

Four types are commonly observed:

• Kerasin- contains Lignoceric acid.
• Cerebron- Contains cerebronic acid. -Nervon- contains Nervonic acid.
• Oxynervon- contains hydroxy derivative of nervonic acid.

Acidic Glycosphingolipids

• Gangliosides are all negatively charged at physiological pH.
• They are negatively charged at physiological pH
• The negative charge is imparted by N- acetyl Neuraminic acid(Sialic acid)
• Brain gangliosides may contain up to four Sialic acid residues and based on that they are-GM, GD, GT and GQ, containing 1,2,3 or 4 Sialic acid residues

- Four important types of Gm series are:

-  GM1, GM2 and GM3

• GM1 is complex of all

Functions of Glycosphingolipids:

• They occur particularly in the outer leaflet of the plasma membrane, where they contribute to cell surface carbohydrates.
• They act as cell surface receptors for various hormones, and growth factors.
• Play important role in cellular interactions, growth and development.
• They are source of blood group antigens and various embryonic antigens.
• GM1 acts as a receptor for cholera toxin in human intestine.

Sulfolipids

• They are cerebrosides that contain sulfated galactosyl residues.
• They are negatively charged at physiological pH.
• Found predominantly in nerve tissue and kidney.
• Failure of degradation causes them to accumulate in nervous tissues

Amphipathic Lipids

• Fatty acids, phospholipids, sphingolipids, bile salts, and, to a lesser extent, cholesterol contain polar groups.
• Part of the molecule is hydrophobic, or water-insoluble; and part is hydrophilic, or water-soluble.

Such molecules are described as amphipathic:

• They become oriented at oil water interfaces with the polar group in the water phase and the nonpolar group in the oil phase.
• A bilayer of such amphipathic lipids is the basic structure in biologic membranes.

Lipids Part II

• Liposomes May be formed by sonicating an amphipathic lipid in an aqueous medium.
• They consist of spheres of lipid bilayers that enclose part of the aqueous medium.
• Liposomes are of potential clinical use-
  • particularly when combined with tissue-specific antibodies-as carriers of drugs in the circulation,
  • targeted to specific organs, eg, in cancer therapy.
  • In addition, they are used for gene transfer into vascular cells and as carriers for topical and transdermal delivery of drugs and.Cosmetics

Emulsions

• Are much larger particles.
• Formed usually by nonpolar lipids in an aqueous medium.
• These are stabilized by emulsifying agents such as amphipathic lipids (eg, lecithin), which form a surface layer separating the main bulk of the nonpolar material from the aqueous phase.