Lipids are broadly defined ashydrophobic oramphiphilic small molecules; the amphiphilic nature of some lipids allows them to form structures such asvesicles, multilamellar/unilamellar liposomes, or membranes in an aqueous environment. Biological lipids originate entirely or in part from two distinct types of biochemical subunits or "building-blocks":ketoacyl andisoprene groups.[3] Using this approach, lipids may be divided into eight categories:fatty acyls,glycerolipids,glycerophospholipids,sphingolipids,saccharolipids, andpolyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).[3]
Although the termlipid is sometimes used as a synonym for fats, fats are a subgroup of lipids calledtriglycerides. Lipids also encompass molecules such asfatty acids and their derivatives (including tri-, di-, monoglycerides, and phospholipids), as well as othersterol-containingmetabolites such ascholesterol.[6] Although humans and other mammals use variousbiosynthetic pathways both to break down and to synthesize lipids, some essential lipids cannot be made this way and must be obtained from the diet.
In 1815,Henri Braconnot classified lipids (graisses) in two categories,suifs (solid greases or tallow) andhuiles (fluid oils).[7] In 1823,Michel Eugène Chevreul developed a more detailed classification, including oils, greases, tallow, waxes, resins, balsams and volatile oils (or essential oils).[8][9][10]In 1827,William Prout recognized fat ("oily" alimentary matters), along with protein ("albuminous") and carbohydrate ("saccharine"), as an important nutrient for humans and animals.[11][12]
For a century, chemists regarded "fats" as only simple lipids made of fatty acids and glycerol (glycerides), but new forms were described later.Theodore Gobley (1847) discovered phospholipids in mammalian brain and hen egg, called by him as "lecithins".Thudichum discovered in human brain some phospholipids (cephalin), glycolipids (cerebroside) and sphingolipids (sphingomyelin).[9]
The terms lipoid, lipin, lipide and lipid have been used with varied meanings from author to author.[15] In 1912, Rosenbloom andGies proposed the substitution of "lipoid" by "lipin".[16] In 1920, Bloor introduced a new classification for "lipoids": simple lipoids (greases and waxes), compound lipoids (phospholipoids and glycolipoids), and the derived lipoids (fatty acids,alcohols, sterols).[17][18]
The wordlipide, which stems etymologically from Greek λίπος,lipos 'fat', was introduced in 1923 by the French pharmacologistGabriel Bertrand.[19] Bertrand included in the concept not only the traditional fats (glycerides), but also the "lipoids", with a complex constitution.[9] The wordlipide was unanimously approved by the international commission of theSociété de Chimie Biologique during the plenary session on July 3, 1923. The wordlipide was later anglicized aslipid because of its pronunciation ('lɪpɪd). In French, the suffix-ide, from Ancient Greek -ίδης (meaning 'son of' or 'descendant of'), is always pronounced (ɪd).
In 1947,T. P. Hilditch defined "simple lipids" as greases and waxes (true waxes, sterols, alcohols).[20][page needed]
Fatty acyls, a generic term for describing fatty acids, their conjugates and derivatives, are a diverse group of molecules synthesized by chain-elongation of anacetyl-CoA primer withmalonyl-CoA ormethylmalonyl-CoA groups in a process calledfatty acid synthesis.[21][22] They are made of ahydrocarbon chain that terminates with acarboxylic acid group; this arrangement confers the molecule with apolar,hydrophilic end, and a nonpolar,hydrophobic end that isinsoluble in water. The fatty acid structure is one of the most fundamental categories of biological lipids and is commonly used as a building-block of more structurally complex lipids. The carbon chain, typically between four and 24 carbons long,[23] may be saturated orunsaturated, and may be attached tofunctional groups containingoxygen,halogens,nitrogen, andsulfur. If a fatty acid contains a double bond, there is the possibility of either acis ortransgeometric isomerism, which significantly affects the molecule'sconfiguration.Cis-double bonds cause the fatty acid chain to bend, an effect that is compounded with more double bonds in the chain. Three double bonds in 18-carbonlinolenic acid, the most abundant fatty-acyl chains of plantthylakoid membranes, render these membranes highlyfluid despite environmental low-temperatures,[24] and also makes linolenic acid give dominating sharp peaks in high resolution 13-C NMR spectra of chloroplasts. This in turn plays an important role in the structure and function of cell membranes.[25]: 193–5 Most naturally occurring fatty acids are of thecis configuration, although thetrans form does exist in some natural and partially hydrogenated fats and oils.[26]
Glycerolipids are composed of mono-, di-, and tri-substitutedglycerols,[30] the best-known being the fatty acidtriesters of glycerol, calledtriglycerides. The word "triacylglycerol" is sometimes used synonymously with "triglyceride". In these compounds, the three hydroxyl groups of glycerol are each esterified, typically by different fatty acids. Because they function as an energy store, these lipids comprise the bulk of storagefat in animal tissues. The hydrolysis of the ester bonds of triglycerides and the release of glycerol and fatty acids fromadipose tissue are the initial steps in metabolizing fat.[31]: 630–1
Additional subclasses of glycerolipids are represented by glycosylglycerols, which are characterized by the presence of one or moresugar residues attached to glycerol via aglycosidic linkage. Examples of structures in this category are the digalactosyldiacylglycerols found in plant membranes[32] and seminolipid from mammaliansperm cells.[33]
Glycerophospholipids, usually referred to asphospholipids (thoughsphingomyelins are also classified as phospholipids), are ubiquitous in nature and are key components of thelipid bilayer of cells,[34] as well as being involved inmetabolism andcell signaling.[35] Neural tissue (including the brain) contains relatively high amounts of glycerophospholipids, and alterations in their composition has been implicated in various neurological disorders.[36] Glycerophospholipids may be subdivided into distinct classes, based on the nature of the polar headgroup at thesn-3 position of the glycerol backbone ineukaryotes and eubacteria, or thesn-1 position in the case ofarchaebacteria.[37]
Examples of glycerophospholipids found inbiological membranes arephosphatidylcholine (also known as PC, GPCho orlecithin),phosphatidylethanolamine (PE or GPEtn) andphosphatidylserine (PS or GPSer). In addition to serving as a primary component of cellular membranes and binding sites for intra- and intercellular proteins, some glycerophospholipids in eukaryotic cells, such asphosphatidylinositols andphosphatidic acids are either precursors of or, themselves, membrane-derivedsecond messengers.[31]: 844 Typically, one or both of these hydroxyl groups are acylated with long-chain fatty acids, but there are also alkyl-linked and 1Z-alkenyl-linked (plasmalogen) glycerophospholipids, as well as dialkylether variants in archaebacteria.[38]
Sphingolipids are a complicated family of compounds[39] that share a common structural feature, asphingoid base backbone that is synthesizedde novo from the amino acidserine and a long-chain fatty acyl CoA, then converted intoceramides, phosphosphingolipids, glycosphingolipids and other compounds. The major sphingoid base of mammals is commonly referred to assphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of sphingoid base derivatives with anamide-linked fatty acid. The fatty acids are typically saturated or mono-unsaturated with chain lengths from 16 to 26 carbon atoms.[25]: 421–2
The major phosphosphingolipids of mammals aresphingomyelins (ceramide phosphocholines),[40] whereas insects contain mainly ceramide phosphoethanolamines[41] and fungi have phytoceramide phosphoinositols andmannose-containing headgroups.[42] The glycosphingolipids are a diverse family of molecules composed of one or more sugar residues linked via aglycosidic bond to the sphingoid base. Examples of these are the simple and complex glycosphingolipids such ascerebrosides andgangliosides.
Sterols, such ascholesterol and its derivatives, are an important component of membrane lipids,[43] along with the glycerophospholipids and sphingomyelins. Other examples of sterols are thebile acids and their conjugates,[44] which in mammals are oxidized derivatives of cholesterol and are synthesized in the liver. The plant equivalents are thephytosterols, such asβ-sitosterol,stigmasterol, andbrassicasterol; the latter compound is also used as abiomarker foralgal growth.[45] The predominant sterol infungal cell membranes isergosterol.[46]
Sterols aresteroids in which one of the hydrogen atoms is substituted with ahydroxyl group, at position 3 in the carbon chain. They have in common with steroids the same fused four-ring core structure. Steroids have different biological roles ashormones andsignaling molecules. The eighteen-carbon (C18) steroids include theestrogen family whereas the C19 steroids comprise theandrogens such astestosterone andandrosterone. The C21 subclass includes theprogestogens as well as theglucocorticoids andmineralocorticoids.[2]: 749 Thesecosteroids, comprising various forms ofvitamin D, are characterized by cleavage of the B ring of the core structure.[47]
Prenol lipids are synthesized from the five-carbon-unit precursorsisopentenyl diphosphate anddimethylallyl diphosphate, which are produced mainly via themevalonic acid (MVA) pathway.[48] The simple isoprenoids (linear alcohols, diphosphates, etc.) are formed by the successive addition of C5 units, and are classified according to number of theseterpene units. Structures containing greater than 40 carbons are known as polyterpenes.Carotenoids are important simple isoprenoids that function asantioxidants and as precursors ofvitamin A.[49] Another biologically important class of molecules is exemplified by thequinones andhydroquinones, which contain an isoprenoid tail attached to a quinonoid core of non-isoprenoid origin.[50]Vitamin E andvitamin K, as well as theubiquinones, are examples of this class. Prokaryotes synthesize polyprenols (calledbactoprenols) in which the terminal isoprenoid unit attached to oxygen remains unsaturated, whereas in animal polyprenols (dolichols) the terminal isoprenoid is reduced.[51]
Structure of the saccharolipid Kdo2-lipid A.[52]Glucosamine residues in blue,Kdo residues in red,acyl chains in black andphosphate groups in green.
Saccharolipids describe compounds in which fatty acids are linked to a sugar backbone, forming structures that are compatible with membrane bilayers. In the saccharolipids, amonosaccharide substitutes for the glycerol backbone present in glycerolipids and glycerophospholipids. The most familiar saccharolipids are the acylatedglucosamine precursors of theLipid A component of thelipopolysaccharides inGram-negative bacteria. Typical lipid A molecules aredisaccharides of glucosamine, which are derivatized with as many as seven fatty-acyl chains. The minimal lipopolysaccharide required for growth inE. coli is Kdo2-Lipid A, a hexa-acylated disaccharide of glucosamine that is glycosylated with two 3-deoxy-D-manno-octulosonic acid (Kdo) residues.[52]
Eukaryotic cells feature the compartmentalized membrane-boundorganelles that carry out different biological functions. Theglycerophospholipids are the main structural component ofbiological membranes, as the cellularplasma membrane and the intracellular membranes of organelles; in animal cells, the plasma membrane physically separates theintracellular components from theextracellular environment.[citation needed] The glycerophospholipids areamphipathic molecules (containing both hydrophobic and hydrophilic regions) that contain a glycerol core linked to two fatty acid-derived "tails" by ester linkages and to one "head" group by aphosphate ester linkage.[citation needed] While glycerophospholipids are the major component of biological membranes, other non-glyceride lipid components such assphingomyelin andsterols (mainly cholesterol in animal cell membranes) are also found in biological membranes.[56][2]: 329–331 In plants and algae, the galactosyldiacylglycerols,[57] and sulfoquinovosyldiacylglycerol,[32] which lack a phosphate group, are important components of membranes of chloroplasts and related organelles and are among the most abundant lipids in photosynthetic tissues, including those of higher plants, algae and certain bacteria.[58]
Plant thylakoid membranes have the largest lipid component of a non-bilayer forming monogalactosyl diglyceride (MGDG), and little phospholipids; despite this unique lipid composition, chloroplast thylakoid membranes have been shown to contain a dynamic lipid-bilayer matrix as revealed by magnetic resonance and electron microscope studies.[59]
A biological membrane is a form oflamellar phaselipid bilayer. The formation of lipid bilayers is an energetically preferred process when theglycerophospholipids described above are in an aqueous environment.[2]: 333–4 This is known as thehydrophobic effect. In an aqueous system, the polar heads of lipids align towards the polar, aqueous environment, while the hydrophobic tails minimize their contact with water and tend to cluster together, forming avesicle; depending on theconcentration of the lipid, this biophysical interaction may result in the formation ofmicelles,liposomes, orlipid bilayers. Other aggregations are also observed and form part of the polymorphism ofamphiphile (lipid) behavior.Phase behavior is an area of study withinbiophysics.[60][61] Micelles and bilayers form in the polar medium by a process known as the hydrophobic effect.[62] When dissolving a lipophilic or amphiphilic substance in a polar environment, the polar molecules (i.e., water in an aqueous solution) become more ordered around the dissolved lipophilic substance, since the polar molecules cannot formhydrogen bonds to the lipophilic areas of the amphiphile. So in an aqueous environment, the water molecules form an ordered "clathrate" cage around the dissolved lipophilic molecule.[63]
The formation of lipids intoprotocell membranes represents a key step in models ofabiogenesis, the origin of life.[64]
Triglycerides, stored in adipose tissue, are a major form of energy storage both in animals and plants. They are a major source of energy in aerobic respiration. The complete oxidation of fatty acids releases about 38 kJ/g (9 kcal/g), compared with only 17 kJ/g (4 kcal/g) for the oxidative breakdown ofcarbohydrates andproteins. Theadipocyte, or fat cell, is designed for continuous synthesis and breakdown of triglycerides in animals, with breakdown controlled mainly by the activation of hormone-sensitive enzymelipase.[65] Migratory birds that must fly long distances without eating use triglycerides to fuel their flights.[2]: 619
Evidence has emerged showing thatlipid signaling is a vital part of thecell signaling.[66][67][68][69] Lipid signaling may occur via activation ofG protein-coupled ornuclear receptors, and members of several different lipid categories have been identified as signaling molecules andcellular messengers.[70] These includesphingosine-1-phosphate, a sphingolipid derived from ceramide that is a potent messenger molecule involved in regulating calcium mobilization,[71] cell growth, and apoptosis;[72]diacylglycerol and thephosphatidylinositol phosphates (PIPs), involved in calcium-mediated activation ofprotein kinase C;[73] theprostaglandins, which are one type of fatty-acid derived eicosanoid involved ininflammation andimmunity;[74] the steroid hormones such asestrogen,testosterone andcortisol, which modulate a host of functions such as reproduction, metabolism and blood pressure; and theoxysterols such as 25-hydroxy-cholesterol that areliver X receptoragonists.[75] Phosphatidylserine lipids are known to be involved in signaling for the phagocytosis of apoptotic cells or pieces of cells. They accomplish this by being exposed to the extracellular face of the cell membrane after the inactivation offlippases which place them exclusively on the cytosolic side and the activation of scramblases, which scramble the orientation of the phospholipids. After this occurs, other cells recognize the phosphatidylserines and phagocytosize the cells or cell fragments exposing them.[76]
The "fat-soluble" vitamins (A,D,E andK) – which areisoprene-based lipids – are essential nutrients stored in the liver and fatty tissues, with a diverse range of functions.Acyl-carnitines are involved in the transport and metabolism of fatty acids in and out of mitochondria, where they undergobeta oxidation.[77] Polyprenols and their phosphorylated derivatives also play important transport roles, in this case the transport ofoligosaccharides across membranes. Polyprenol phosphate sugars and polyprenol diphosphate sugars function in extra-cytoplasmic glycosylation reactions, in extracellular polysaccharide biosynthesis (for instance,peptidoglycan polymerization in bacteria), and in eukaryotic protein N-glycosylation.[78][79]Cardiolipins are a subclass of glycerophospholipids containing four acyl chains and three glycerol groups that are particularly abundant in the inner mitochondrial membrane.[80][81] They are believed to activate enzymes involved withoxidative phosphorylation.[82] Lipids also form the basis of steroid hormones.[83]
The major dietary lipids for humans and other animals are animal and plant triglycerides, sterols, and membrane phospholipids. The process of lipid metabolism synthesizes and degrades the lipid stores and produces the structural and functional lipids characteristic of individual tissues.
In animals, when there is an oversupply of dietary carbohydrate, the excess carbohydrate is converted to triglycerides. This involves the synthesis of fatty acids fromacetyl-CoA and theesterification of fatty acids in the production of triglycerides, a process calledlipogenesis.[2]: 634 Fatty acids are made byfatty acid synthases that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the acetyl group, reduce it to an alcohol,dehydrate it to analkene group and then reduce it again to analkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional protein,[84] while in plantplastids and bacteria separate enzymes perform each step in the pathway.[85][86] The fatty acids may be subsequently converted to triglycerides that are packaged inlipoproteins and secreted from the liver.
Triglyceride synthesis takes place in theendoplasmic reticulum by metabolic pathways in which acyl groups in fatty acyl-CoAs are transferred to the hydroxyl groups of glycerol-3-phosphate and diacylglycerol.[2]: 733–9
Beta oxidation is the metabolic process by which fatty acids are broken down in themitochondria or inperoxisomes to generateacetyl-CoA. For the most part, fatty acids are oxidized by a mechanism that is similar to, but not identical with, a reversal of the process of fatty acid synthesis. That is, two-carbon fragments are removed sequentially from the carboxyl end of the acid after steps ofdehydrogenation,hydration, andoxidation to form abeta-keto acid, which is split bythiolysis. The acetyl-CoA is then ultimately converted intoadenosine triphosphate (ATP), CO2, and H2O using thecitric acid cycle and theelectron transport chain. Hence the citric acid cycle can start at acetyl-CoA when fat is being broken down for energy if there is little or no glucose available. The energy yield of the complete oxidation of the fatty acid palmitate is 106 ATP.[2]: 625–6 Unsaturated and odd-chain fatty acids require additional enzymatic steps for degradation.
Most of the fat found in food is in the form of triglycerides, cholesterol, and phospholipids. Some dietary fat is necessary to facilitate absorption of fat-soluble vitamins (A,D,E, andK) andcarotenoids.[91]: 903 Humans and other mammals have a dietary requirement for certain essential fatty acids, such aslinoleic acid (anomega-6 fatty acid) andalpha-linolenic acid (an omega-3 fatty acid) because they cannot be synthesized from simple precursors in the diet.[2]: 643 Both of these fatty acids are 18-carbonpolyunsaturated fatty acids differing in the number and position of the double bonds. Mostvegetable oils are rich in linoleic acid (safflower,sunflower, andcorn oils). Alpha-linolenic acid is found in the green leaves of plants and in some seeds, nuts, and legumes (in particularflax,rapeseed,walnut, andsoy).[92]Fish oils are particularly rich in the longer-chain omega-3 fatty acidseicosapentaenoic acid anddocosahexaenoic acid.[91]: 388 Many studies have shown positive health benefits associated with consumption of omega-3 fatty acids on infant development, cancer, cardiovascular diseases, and various mental illnesses (such as depression, attention-deficit hyperactivity disorder, and dementia).[93][94]
Results from recent clinical trials have linked long-term variation in lipids, including LDL and triglycerides, with risk of cardiovascular disease, diabetes, or heart failure.[98][99][100] Excessive lipid variability has been linked to oxidative stress and endothelial dysfunction.[101]
A few studies have suggested that total dietary fat intake is linked to an increased risk of obesity[102][103] and diabetes.[104] Others, including the Women's Health Initiative Dietary Modification Trial, an eight-year study of 49,000 women, the Nurses' Health Study, and the Health Professionals Follow-up Study, revealed no such links.[105][106] None of these studies suggested any connection between percentage of calories from fat and risk of cancer, heart disease, or weight gain. The Nutrition Source,[107] a website maintained by the department of nutrition at theT. H. Chan School of Public Health atHarvard University, summarizes the current evidence on the effect of dietary fat: "Detailed research—much of it done at Harvard—shows that the total amount of fat in the diet isn't really linked with weight or disease."[108]
Phenolic lipid – Class of organic compounds, a class of natural products composed of long aliphatic chains and phenolic rings that occur in plants, fungi and bacteria
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LIPID MAPS – Comprehensive lipid and lipid-associated gene/protein databases.
LipidBank – Japanese database of lipids and related properties, spectral data and references.
General
ApolloLipids – Provides dyslipidemia and cardiovascular disease prevention and treatment information as well as continuing medical education programs
National Lipid Association – Professional medical education organization for health care professionals who seek to prevent morbidity and mortality stemming from dyslipidemias and other cholesterol-related disorders.
