Cell signaling

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cell_signaling

In biology, cell signaling (cell signalling in British English), or cell-cell communication, governs the basic activities of cells and coordinates multiple-cell actions. A signal is an entity that codes or conveys information. Biological processes are complex molecular interactions that involve many signals. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis. Errors in signaling interactions and cellular information processing may cause diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, clinicians may treat diseases more effectively and, theoretically, researchers may develop artificial tissues.

All cells receive and respond to signals from their surroundings. This is accomplished by a variety of signal molecules that are secreted or expressed on the surface of one cell and bind to a receptor expressed by the other cells, thereby integrating and coordinating the function of the many individual cells that make up organisms. Each cell is programmed to respond to specific extracellular signal molecules. Extracellular signaling usually entails the following steps:

1. Synthesis and release of the signaling molecule by the signaling cell;
2. Transport of the signal to the target cell;
3. Binding of the signal by a specific receptor leading to its activation;
4. Initiation of signal-transduction pathways.

Signaling agents could be physical agents like mechanical pressure, voltage, temperature, and light or chemical agents like peptides, steroids, terpenoids, etc. It may be food material or pathogen-associated patterns, or it may be oxygen or carbon dioxide levels or specially biosynthesised signaling molecules like hormones and ferromones (ektohormones). Signaling molecules vary greatly in their physio-chemical properties such as solubility (hydrophobic or hydrophillic). Some of the signaling molecules are gaseous, such as nitric oxide. Additionally, proteins on the surface of neighboring cells could also be signals.

Synthesis involves various biosynthetic pathways, and happens in specific time and place. Signal molecules may be released from the cell and sometimes they are not released at all, such as cellular localization signals and DNA damage signals. Such intracellular signaling networks work within the cell. Signal molecules that can be released through various ways like membrane-diffusion, exocytosis or cell damage. In some cases the signal molecules remain attached with cell-surface, a mode that helps in juxtacrine signaling (discussed below). Sometimes signal molecules require activation, such as through proteolytic cleavage or covalent modifications.

The ultimate path of the signal may be intracellular or intercellular. The intercellular signaling is also called cell-to-cell communication. It can be short or long distance. Based on nature of this path of signal molecule from source to target cell; the signaling pathways are classified into autocrine, juxtacrine, intracrine, paracrine and endocrine.

Receptors play a key role in cell signaling. Receptors help in recognising the signal molecule (ligand). However some receptor molecules respond to physical agents (voltage, light, etc). Receptor molecules are generally proteins. Receptors may be located at cell surface, or interior of the cell such as cytosol, the organelles and nucleus (especially the transcription factors). Usually the cell surface receptors bind membrane-impermeable signal molecules, but sometimes they also interact with membrane permeable signal molecules. A key step in signaling is removal and degradation of the signal molecule. Sometimes the receptor is also degraded. Neurotransmitter reuptake is a mechanism of signaling molecule removal that is commonly seen in nervous system, and is a target of some class of prescription psychiatric medications.

Binding with the ligand causes conformational change in the receptor, which leads to further transmission of signaling. Due to conformational change, the receptor may either show an enzymic activity (called enzymic receptor), or a ion channel opening or closing activity (called a channel receptor). Sometimes the receptors themselves do not contain enzymatic or channel-like domains but they are linked with enzyme or transporter. Some receptors (like the nuclear-cytoplasmic superfamily) have a different mechanism. Once they bind with signal, they change their DNA binding properties and cellular localisation to the nucleus.

Result of enzymatic activity of the receptor usually leads to recruitment of additional molecular changes thus causing a signal transduction "cascade". These intermediates often forms a second messenger system. Within the signal transduction cascade there may be enzymes and transporters which work similar way as receptors. Enzymatic activities include covalent modifications like proteolytic cleavage, phosphorylation/dephosphorylation, methylation/demethylation, ubiquitinylation/deubiquitinylation etc. These changes help regulate the propagation of the signal through the cell. An important phenomena that happens in the intracellular portion of signaling is signal amplification. During signal amplification, a few number of receptors are initially activated. The intracellular response results in multiple secondary messengers to be activated, thereby amplifying the initial signal.

Systems biology studies the underlying structure of cell-signaling networks and how changes in these networks may affect the transmission and flow of information (signal transduction). Such networks are complex systems in their organization and may exhibit a number of emergent properties, including bistability and ultrasensitivity. Analysis of cell-signaling networks requires a combination of experimental and theoretical approaches, including the development and analysis of simulations and modeling. Long-range allostery is often a significant component of cell-signaling events.

Between individual organisms of same species

Figure 1. Example of signaling between bacteria. Salmonella enteritidis uses N-Acyl homoserine lactone for Quorum sensing

Cell signaling has been most extensively studied in the context of human diseases and signaling between cells of a single organism. However, cell signaling may also occur between the cells of two different individuals of the same species. In many mammals, early embryo cells exchange signals with cells of the uterus. In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) into their environment. The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.

Classification

Cell signaling can be classified as either mechanical or biochemical based on the type of the signal. Mechanical signals are the forces exerted on the cell and the forces produced by the cell. These forces can both be sensed and responded to by the cells. Biochemical signals are biochemical molecules such as proteins, lipids, ions, and gases. These signals can be categorized based on the distance between signaling and responder cells. Signaling within, between, and amongst cells is subdivided into the following classifications:

• Intracrine signals are produced by the target cell that stay within the target cell.
• Autocrine signals are produced by the target cell, are secreted, and affect the target cell itself via receptors. Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example of this are immune cells.
• Juxtacrine signals target adjacent (touching) cells. These signals are transmitted along cell membranes via protein or lipid components integral to the membrane and are capable of affecting either the emitting cell or cells immediately adjacent.
• Paracrine signals target cells in the vicinity of the emitting cell. Neurotransmitters represent an example.
• Endocrine signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all parts of the body.

Figure 2. Notch-mediated juxtacrine signal between adjacent cells.

Cells communicate with each other via direct contact (juxtacrine signaling), over short distances (paracrine signaling), or over large distances and/or scales (endocrine signaling).

Some cell–cell communication requires direct cell–cell contact. Some cells can form gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. In cardiac muscle, gap junctions between adjacent cells allow for action potential propagation from the cardiac pacemaker region of the heart to spread and coordinate the contraction of the heart.

The notch signaling mechanism is an example of juxtacrine signaling (also known as contact-dependent signaling) in which two adjacent cells must make physical contact in order to communicate. This requirement for direct contact allows for very precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell.

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. Neurotransmitters represent another example of a paracrine signal. Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling. Active species of oxygen and nitric oxide can also act as cellular messengers. This process is dubbed redox signaling.

In multicellular organisms

In a multicellular organism, signaling between cells occurs either through release into the extracellular space, divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling. Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells. Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects.

A particular molecule is generally used in diverse modes of signaling, and therefore a classification by mode of signaling is not possible. At least three important classes of signaling molecules are widely recognized, although non-exhaustive and with imprecise boundaries, as such membership is non-exclusive and depends on the context:

• Hormones are the major signaling molecules of the endocrine system, though they often regulate each other's secretion via local signaling (e.g. islet of Langerhans cells), and most are also expressed in tissues for local purposes (e.g. angiotensin) or failing that, structurally related molecules are (e.g. PTHrP).
• Neurotransmitters are signaling molecules of the nervous system, also including neuropeptides and neuromodulators. Neurotransmitters like the catecholamines are also secreted by the endocrine system into the systemic circulation.
• Cytokines are signaling molecules of the immune system, with a primary paracrine or juxtacrine role, though they can during significant immune responses have a strong presence in the circulation, with systemic effect (altering iron metabolism or body temperature). Growth factors can be considered as cytokines or a different class.

Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, Vasopressin, Acetylcholine), while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic acid), but important exceptions to both are numerous, and a same molecule can act both via surface receptor or in an intracrine manner to different effects. In intracrine signaling, once inside the cell, a signaling molecule can bind to intracellular receptors, other elements, or stimulate enzyme activity (e.g. gasses). The intracrine action of peptide hormones remains a subject of debate.

Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon monoxide.

In plants

Signaling in plants happen through plant hormones, Phytochromes, Cryptochromes etc.

Important families of plant hormones are Auxin, cytokinin, gibberelline, ethyline, jasmonic acid, salicylic acid, strigolactones, polyamines, nitric oxide, peptide hormones etc. Translocation of RNA also has been reported.

Signaling receptors

Transmembrane receptor working principle

Cells receive information from their neighbors through a class of proteins known as receptors. Receptors may bind with some molecules (ligands) or may interact with physical agents like light, mechanical temperature, pressure, etc. Some receptors are membrane bound and some receptors are cytosolic. A large number of cytosolic receptors belong to nuclear-cytoplasmic-superfamily.

Some important transmembrane receptors are Voltage gated ion channels , Ligand gated ion channels, Seven helix receptors or GPCRs, Two component receptors, Cytokine receptors, Receptor tyrosine kinase, Tyrosine kinase linked receptor, Receptor Serine threonine kinase, Receptor tyrosine phosphatase, Receptor guanylyl cyclase, Sphingomylinase linked receptor, Integrin, selectin, Cadherin, etc.

Notch is a cell surface protein that functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. Ligand receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication.

As shown in Figure 2 (above; left), notch acts as a receptor for ligands that are expressed on adjacent cells. While some receptors are cell-surface proteins, others are found inside cells. For example, estrogen is a hydrophobic molecule that can pass through the lipid bilayer of the membranes. As part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be activated by estrogen produced in the ovaries.

A number of transmembrane receptors for small molecules and peptide hormones, as well as intracellular receptors for steroid hormones exist, giving cells the ability to respond to a great number of hormonal and pharmacological stimuli. In diseases, often, proteins that interact with receptors are aberrantly activated, resulting in constitutively activated downstream signals.

For several types of intercellular signaling molecules that are unable to permeate the hydrophobic cell membrane due to their hydrophilic nature, the target receptor is expressed on the membrane. When such a signaling molecule activates its receptor, the signal is carried into the cell usually by means of a second messenger such as cAMP.

The receptor-ligand interaction can be classified as:

• Agonism: it is when a ligand increases the activity of a ligand. Agonism is demonstrated in absence of any other competing ligand for the same receptor.
• Inverse agonism: When a receptor is constitutively active, and the constitutive activity is suppressed or inhibited by the ligand
• Antagonism: In presence of the agonist ligand, the antagonist molecule hinder the activation of the receptor by the ligand.
• Partial agonism: it is when a ligand shows agonism, but in spite of increasing dosage of the ligand, the receptor activation does not reach the full activation state.
• Partial inverse agonism: When a receptor is constitutively active, and in spite of increasing dosage of the ligand, the receptor activity decreases but does not become fully inactive.
• Protean agonism: Protean agonists can act both as an agonist or an inverse agonist based on whether the receptor is already inactive (quiescent) or already active.
• Biased agonism : when a receptor acts on more than one variants of next molecule in transduction chain; and binding with one agonist favours only one of the possible transduction pathway.

Signaling pathways

Brief overview of some signaling pathways (based on receptor families)

Receptor Family	Example of Ligands/ activators (Bracket: receptor for it)	Example of effectors	Further downstream effects
Ligand Gated Ion Channels	Acetylcholine (Such as Nicotinic acetylcholine receptor),	Changes in membrane permeability	Change in membrane potential
Seven Helix Receptor	Light(Rhodopsin), Dopamine (Dopamine receptor), GABA (GABA receptor), Prostaglandin (prostaglandin receptor) etc.	Trimeric G protein	Adenylate Cyclase, cGMP phosphodiesterase, G-protein gated ion channel, etc.
Frizzled (Special type of 7Helix receptor)	Wnt	Dishevelled, axin - APC, GSK3-beta - Beta catenin	Gene expression
Two Component	Diverse activators	Histidine Kinase	Response Regulator - flagellar movement, Gene expression
Receptor Tyrosine Kinase	Insulin (insulin receptor), EGF (EGF receptor), FGF-Alpha, FGF-Beta, etc (FGF-receptors)	Ras, MAP-kinases, PLC, PI3-Kinase	Gene expression change
Cytokine receptors	Erythropoietin, Growth Hormone (Growth Hormone Receptor), IFN-Gamma (IFN-Gamma receptor) etc	JAK kinase	STAT transcription factor - Gene expression
Tyrosine kinase Linked- receptors	MHC-peptide complex - TCR, Antigens - BCR	Cytoplasmic Tyrosine Kinase	Gene expression
Receptor Serine/Threonine Kinase	Activin(activin receptor), Inhibin, Bone-morphogenetic protein(BMP Receptor), TGF-beta	Smad transcription factors	Control of gene expression
Membrane Guanylyl Cyclase	Atrial natriuretic peptide, Sea urching egg peptide etc.	cGMP	Regulation of Kinases and channels- Diverse actions
Cytoplasmic Guanylyl cyclase	Nitric Oxide(Nitric oxide receptor)	cGMP	Regulation of cGMP Gated channels, Kinases
Sphingomyelinase linked receptors	IL-1(IL-1 receptor), TNF (TNF-receptors)	Ceramide activated kinases	Gene expression
Integrins	Fibronectins, other extracellular matrix proteins	Nonreceptor tyrosine kinase	Diverse response
Cytoplasmic Steroid receptors	Steroid hormones, Thyroid hormones, Retinoic acid etc	Work as/ interact with transcription factors	Gene expression

Overview of signal transduction pathways

 

Figure 3. Key components of a signal transduction pathway (MAPK/ERK pathway shown)

In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For example, the neurotransmitter GABA can activate a cell surface receptor that is part of an ion channel. GABA binding to a GABA_A receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABA_A receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate physiological effect of the ligand on the cell's behavior is produced. Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway.

In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. As shown in Figure 2, the activation of Notch can cause the Notch protein to be altered by a protease. Part of the Notch protein is released from the cell surface membrane and takes part in gene regulation. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types. Emerging methods for single-cell mass-spectrometry analysis promise to enable studying signal transduction with single-cell resolution.

A more complex signal transduction pathway is shown in Figure 3. This pathway involves changes of protein–protein interactions inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. Several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. This phosphorylation can generate a binding site for a different protein and thus induce protein–protein interaction. In Figure 3, the ligand (called epidermal growth factor, or EGF) binds to the receptor (called EGFR). This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an adaptor protein (GRB2), which couples the signal to further downstream signaling processes. For example, one of the signal transduction pathways that are activated is called the mitogen-activated protein kinase (MAPK) pathway. The signal transduction component labeled as "MAPK" in the pathway was originally called "ERK," so the pathway is called the MAPK/ERK pathway. The MAPK protein is an enzyme, a protein kinase that can attach phosphate to target proteins such as the transcription factor MYC and, thus, alter gene transcription and, ultimately, cell cycle progression. Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal transduction pathway.

Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance, the hedgehog protein activates different genes, depending on the amount of hedgehog protein present.

Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways.

Intra- and inter-species signaling

Molecular signaling can occur between different organisms, whether unicellular or multicellular. The emitting organism produces the signaling molecule, secretes it into the environment, where it diffuses, and it is sensed or internalized by the receiving organism. In some cases of interspecies signaling, the emitting organism can actually be a host of the receiving organism, or vice versa.

Intraspecies signaling occurs especially in bacteria, yeast, social insects, but also many vertebrates. The signaling molecules used by multicellular organisms are often called pheromones. They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction. In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc. In quorum sensing, which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response. In this context, the signaling molecules are called autoinducers. This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. Bacteria also use contact-dependent signaling, notably to limit their growth.

Molecular signaling can also occur between individuals of different species. This has been particularly studied in bacteria. Different bacterial species can coordinate to colonize a host and participate in common quorum sensing. Therapeutic strategies to disrupt this phenomenon are being investigated. Interactions mediated through signaling molecules are also thought to occur between the gut flora and their host, as part of their commensal or symbiotic relationship. Gram negative microbes deploy bacterial outer membrane vesicles for intra- and inter-species signaling in natural environments and at the host-pathogen interface.

Additionally, interspecies signaling occurs between multicellular organisms. In Vespa mandarinia, individuals release a scent that directs the colony to a food source.

In plants, inter-species signaling is particularly important in mycorrhizal symbiosis and root nodule symbiosis. In both symbioses, Receptor-like kinase (RLK), G-proteins, MAP-kinases and Ca²⁺ plays a very important role.

Computational models

Recent approaches to better understand elements of pathway crosstalk, complex ligand-receptor binding, and signaling network dynamics have been aided by the use of systems biology approaches. Computational models often take aim at compiling information from published literature to generate a coherent set of signaling components and their associated interactions. The development of computational models allows for a more in-depth probing of cell signaling pathways at a global level by manipulating different variables and systemically evaluating the resulting response. The use of analytical models for the study of signal transduction has been heavily applied in the fields of pharmacology and drug discovery to assess receptor-ligand interactions and pharmacokinetics as well as the flow of metabolites in large networks. A commonly applied strategy to model cell signaling mechanisms is through the use of ordinary differential equation (ODE) models by expressing the time-dependent concentration of a signaling molecule as a function of other molecules downstream and/or upstream within the pathway. ODE models have already been applied for dynamic analysis of the Mitogen-activated protein kinase, Estrogen receptor alpha, and MTOR signaling pathways among numerous others.

Lipid

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Lipid 

 

Structures of some common lipids. At the top are cholesterol and oleic acid. The middle structure is a triglyceride composed of oleoyl, stearoyl, and palmitoyl chains attached to a glycerol backbone. At the bottom is the common phospholipid phosphatidylcholine.

In biology and biochemistry, a lipid is a macro biomolecule that is soluble in nonpolar solvents. Non-polar solvents are typically hydrocarbons used to dissolve other naturally occurring hydrocarbon lipid molecules that do not (or do not easily) dissolve in water, including fatty acids, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E, and K), monoglycerides, diglycerides, triglycerides, and phospholipids.

The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries as well as in nanotechnology.

Scientists sometimes define lipids as hydrophobic or amphiphilic small molecules; the amphiphilic nature of some lipids allows them to form structures such as vesicles, 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 and isoprene groups. Using this approach, lipids may be divided into eight categories: fatty acids, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).

Although the term "lipid" is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides. Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, monoglycerides, and phospholipids), as well as other sterol-containing metabolites such as cholesterol. Although humans and other mammals use various biosynthetic pathways both to break down and to synthesize lipids, some essential lipids can't be made this way and must be obtained from the diet.

History

Lipid may be regarded as organic substances relatively insoluble in water, soluble in organic solvents(alcohol, ether etc.) actually or potentially related to fatty acid and utilized by the living cells.

In 1815, Henri Braconnot classified lipids (graisses) in two categories, suifs (solid greases or tallow) and huiles (fluid oils). In 1823, Michel Eugène Chevreul developed a more detailed classification, including oils, greases, tallow, waxes, resins, balsams and volatile oils (or essential oils).

The first successful synthesis of a triglyceride molecule was by Théophile-Jules Pelouze in 1844, when he produced tributyrin by reacting butyric acid with glycerin in the presence of concentrated sulfuric acid. Several years later, Marcellin Berthelot, one of Pelouze's students, synthesized tristearin and tripalmitin by reaction of the analogous fatty acids with glycerin in the presence of gaseous hydrogen chloride at high temperature.

In 1827, William Prout recognized fat ("oily" alimentary matters), along with protein ("albuminous") and carbohydrate ("saccharine"), as an important nutrient for humans and animals.

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).

The terms lipoid, lipin, lipide and lipid have been used with varied meanings from author to author. In 1912, Rosenbloom and Gies proposed the substitution of "lipoid" by "lipin". 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).

The word lipide, which stems etymologically from Greek λίπος, lipos 'fat', was introduced in 1923 by the French pharmacologist Gabriel Bertrand. Bertrand included in the concept not only the traditional fats (glycerides), but also the "lipoids", with a complex constitution. Even though the word lipide was unanimously approved by the international commission of the Société de Chimie Biologique during the plenary session on the July 3, 1923. The word lipide was later anglicized as lipid 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 divided lipids into "simple lipids", with greases and waxes (true waxes, sterols, alcohols).

Categories

Lipids have been classified into eight categories by the Lipid MAPS consortium as follows:

Fatty acids

I₂ - Prostacyclin (an example of a prostaglandin, an eicosanoid fatty acid)

 

LTB₄ (an example of a leukotriene, an eicosanoid fatty acid)

Fatty acids, or fatty acid residues when they are part of a lipid, are a diverse group of molecules synthesized by chain-elongation of an acetyl-CoA primer with malonyl-CoA or methylmalonyl-CoA groups in a process called fatty acid synthesis. They are made of a hydrocarbon chain that terminates with a carboxylic acid group; this arrangement confers the molecule with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble 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, may be saturated or unsaturated, and may be attached to functional groups containing oxygen, halogens, nitrogen, and sulfur. If a fatty acid contains a double bond, there is the possibility of either a cis or trans geometric isomerism, which significantly affects the molecule's configuration. 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-carbon linolenic acid, the most abundant fatty-acyl chains of plant thylakoid membranes, render these membranes highly fluid despite environmental low-temperatures, 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. Most naturally occurring fatty acids are of the cis configuration, although the trans form does exist in some natural and partially hydrogenated fats and oils.

Examples of biologically important fatty acids include the eicosanoids, derived primarily from arachidonic acid and eicosapentaenoic acid, that include prostaglandins, leukotrienes, and thromboxanes. Docosahexaenoic acid is also important in biological systems, particularly with respect to sight. Other major lipid classes in the fatty acid category are the fatty esters and fatty amides. Fatty esters include important biochemical intermediates such as wax esters, fatty acid thioester coenzyme A derivatives, fatty acid thioester ACP derivatives and fatty acid carnitines. The fatty amides include N-acyl ethanolamines, such as the cannabinoid neurotransmitter anandamide.

Glycerolipids

Example of an unsaturated fat triglyceride (C₅₅H₉₈O₆). Left part: glycerol; right part, from top to bottom: palmitic acid, oleic acid, alpha-linolenic acid.

Glycerolipids are composed of mono-, di-, and tri-substituted glycerols, the best-known being the fatty acid triesters of glycerol, called triglycerides. 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 storage fat in animal tissues. The hydrolysis of the ester bonds of triglycerides and the release of glycerol and fatty acids from adipose tissue are the initial steps in metabolizing fat.

Additional subclasses of glycerolipids are represented by glycosylglycerols, which are characterized by the presence of one or more sugar residues attached to glycerol via a glycosidic linkage. Examples of structures in this category are the digalactosyldiacylglycerols found in plant membranes and seminolipid from mammalian sperm cells.

Glycerophospholipids

Phosphatidylethanolamine

Glycerophospholipids, usually referred to as phospholipids (though sphingomyelins are also classified as phospholipids), are ubiquitous in nature and are key components of the lipid bilayer of cells, as well as being involved in metabolism and cell signaling. Neural tissue (including the brain) contains relatively high amounts of glycerophospholipids, and alterations in their composition has been implicated in various neurological disorders. Glycerophospholipids may be subdivided into distinct classes, based on the nature of the polar headgroup at the sn-3 position of the glycerol backbone in eukaryotes and eubacteria, or the sn-1 position in the case of archaebacteria.

Examples of glycerophospholipids found in biological membranes are phosphatidylcholine (also known as PC, GPCho or lecithin), phosphatidylethanolamine (PE or GPEtn) and phosphatidylserine (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 as phosphatidylinositols and phosphatidic acids are either precursors of or, themselves, membrane-derived second messengers. 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.

Sphingolipids

Sphingomyelin

Sphingolipids are a complicated family of compounds that share a common structural feature, a sphingoid base backbone that is synthesized de novo from the amino acid serine and a long-chain fatty acyl CoA, then converted into ceramides, phosphosphingolipids, glycosphingolipids and other compounds. The major sphingoid base of mammals is commonly referred to as sphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of sphingoid base derivatives with an amide-linked fatty acid. The fatty acids are typically saturated or mono-unsaturated with chain lengths from 16 to 26 carbon atoms.

The major phosphosphingolipids of mammals are sphingomyelins (ceramide phosphocholines), whereas insects contain mainly ceramide phosphoethanolamines and fungi have phytoceramide phosphoinositols and mannose-containing headgroups. The glycosphingolipids are a diverse family of molecules composed of one or more sugar residues linked via a glycosidic bond to the sphingoid base. Examples of these are the simple and complex glycosphingolipids such as cerebrosides and gangliosides.

Sterols

Chemical structure of cholesterol.

Sterols, such as cholesterol and its derivatives, are an important component of membrane lipids, along with the glycerophospholipids and sphingomyelins. Other examples of sterols are the bile acids and their conjugates, which in mammals are oxidized derivatives of cholesterol and are synthesized in the liver. The plant equivalents are the phytosterols, such as β-sitosterol, stigmasterol, and brassicasterol; the latter compound is also used as a biomarker for algal growth. The predominant sterol in fungal cell membranes is ergosterol.

Sterols are steroids in which one of the hydrogen atoms is substituted with a hydroxyl 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 as hormones and signaling molecules. The eighteen-carbon (C18) steroids include the estrogen family whereas the C19 steroids comprise the androgens such as testosterone and androsterone. The C21 subclass includes the progestogens as well as the glucocorticoids and mineralocorticoids. The secosteroids, comprising various forms of vitamin D, are characterized by cleavage of the B ring of the core structure.

Prenols

Prenol lipid (2E-geraniol)

Prenol lipids are synthesized from the five-carbon-unit precursors isopentenyl diphosphate and dimethylallyl diphosphate that are produced mainly via the mevalonic acid (MVA) pathway. The simple isoprenoids (linear alcohols, diphosphates, etc.) are formed by the successive addition of C5 units, and are classified according to number of these terpene units. Structures containing greater than 40 carbons are known as polyterpenes. Carotenoids are important simple isoprenoids that function as antioxidants and as precursors of vitamin A. Another biologically important class of molecules is exemplified by the quinones and hydroquinones, which contain an isoprenoid tail attached to a quinonoid core of non-isoprenoid origin. Vitamin E and vitamin K, as well as the ubiquinones, are examples of this class. Prokaryotes synthesize polyprenols (called bactoprenols) in which the terminal isoprenoid unit attached to oxygen remains unsaturated, whereas in animal polyprenols (dolichols) the terminal isoprenoid is reduced.

Saccharolipids

Structure of the saccharolipid Kdo₂-lipid A. Glucosamine residues in blue, Kdo residues in red, acyl chains in black and phosphate groups in green.

Saccharolipids describe compounds in which fatty acids are linked to a nucleotide backbone, forming structures that are compatible with membrane bilayers. In the saccharolipids, a monosaccharide substitutes for the glycerol backbone present in glycerolipids and glycerophospholipids. The most familiar saccharolipids are the acylated glucosamine precursors of the Lipid A component of the lipopolysaccharides in Gram-negative bacteria. Typical lipid A molecules are disaccharides of glucosamine, which are derivatized with as many as seven fatty-acyl chains. The minimal lipopolysaccharide required for growth in E. coli is Kdo₂-Lipid A, a hexa-acylated disaccharide of glucosamine that is glycosylated with two 3-deoxy-D-manno-octulosonic acid (Kdo) residues.

Polyketides

Polyketides are synthesized by polymerization of acetyl and propionyl subunits by classic enzymes as well as iterative and multimodular enzymes that share mechanistic features with the fatty acid synthases. They comprise many secondary metabolites and natural products from animal, plant, bacterial, fungal and marine sources, and have great structural diversity. Many polyketides are cyclic molecules whose backbones are often further modified by glycosylation, methylation, hydroxylation, oxidation, or other processes. Many commonly used anti-microbial, anti-parasitic, and anti-cancer agents are polyketides or polyketide derivatives, such as erythromycins, tetracyclines, avermectins, and antitumor epothilones.

Biological functions

Membranes

Eukaryotic cells feature the compartmentalized membrane-bound organelles that carry out different biological functions. The glycerophospholipids are the main structural component of biological membranes, as the cellular plasma membrane and the intracellular membranes of organelles; in animal cells, the plasma membrane physically separates the intracellular components from the extracellular environment. The glycerophospholipids are amphipathic 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 a phosphate ester linkage. While glycerophospholipids are the major component of biological membranes, other non-glyceride lipid components such as sphingomyelin and sterols (mainly cholesterol in animal cell membranes) are also found in biological membranes. In plants and algae, the galactosyldiacylglycerols, and sulfoquinovosyldiacylglycerol, which lack a phosphate group, are important components of membranes of chloroplasts and related organelles and are the most abundant lipids in photosynthetic tissues, including those of higher plants, algae and certain bacteria.

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.

Self-organization of phospholipids: a spherical liposome, a micelle, and a lipid bilayer.

A biological membrane is a form of lamellar phase lipid bilayer. The formation of lipid bilayers is an energetically preferred process when the glycerophospholipids described above are in an aqueous environment. This is known as the hydrophobic 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 a vesicle; depending on the concentration of the lipid, this biophysical interaction may result in the formation of micelles, liposomes, or lipid bilayers. Other aggregations are also observed and form part of the polymorphism of amphiphile (lipid) behavior. Phase behavior is an area of study within biophysics and is the subject of current academic research. Micelles and bilayers form in the polar medium by a process known as the hydrophobic effect. 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 form hydrogen 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.

The formation of lipids into protocell membranes represents a key step in models of abiogenesis, the origin of life.

Energy storage

Triglycerides, stored in adipose tissue, are a major form of energy storage both in animals and plants. They are a major source of energy because carbohydrates are fully reduced structures. In comparison to glycogen which would contribute only half of the energy per its pure mass, triglyceride carbons are all bonded to hydrogens, unlike in carbohydrates. The adipocyte, or fat cell, is designed for continuous synthesis and breakdown of triglycerides in animals, with breakdown controlled mainly by the activation of hormone-sensitive enzyme lipase. The complete oxidation of fatty acids provides high caloric content, about 38 kJ/g (9 kcal/g), compared with 17 kJ/g (4 kcal/g) for the breakdown of carbohydrates and proteins. Migratory birds that must fly long distances without eating use stored energy of triglycerides to fuel their flights.

Signaling

Evidence has emerged showing that lipid signaling is a vital part of the cell signaling. Lipid signaling may occur via activation of G protein-coupled or nuclear receptors, and members of several different lipid categories have been identified as signaling molecules and cellular messengers. These include sphingosine-1-phosphate, a sphingolipid derived from ceramide that is a potent messenger molecule involved in regulating calcium mobilization, cell growth, and apoptosis; diacylglycerol (DAG) and the phosphatidylinositol phosphates (PIPs), involved in calcium-mediated activation of protein kinase C; the prostaglandins, which are one type of fatty-acid derived eicosanoid involved in inflammation and immunity; the steroid hormones such as estrogen, testosterone and cortisol, which modulate a host of functions such as reproduction, metabolism and blood pressure; and the oxysterols such as 25-hydroxy-cholesterol that are liver X receptor agonists. 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 of flippases 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.

Other functions

The "fat-soluble" vitamins (A, D, E and K) – which are isoprene-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 undergo beta oxidation. Polyprenols and their phosphorylated derivatives also play important transport roles, in this case the transport of oligosaccharides 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. Cardiolipins are a subclass of glycerophospholipids containing four acyl chains and three glycerol groups that are particularly abundant in the inner mitochondrial membrane. They are believed to activate enzymes involved with oxidative phosphorylation. Lipids also form the basis of steroid hormones.

Metabolism

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.

Biosynthesis

In animals, when there is an oversupply of dietary carbohydrate, the excess carbohydrate is converted to triglycerides. This involves the synthesis of fatty acids from acetyl-CoA and the esterification of fatty acids in the production of triglycerides, a process called lipogenesis. Fatty acids are made by fatty 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 an alkene group and then reduce it again to an alkane 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, while in plant plastids and bacteria separate enzymes perform each step in the pathway. The fatty acids may be subsequently converted to triglycerides that are packaged in lipoproteins and secreted from the liver.

The synthesis of unsaturated fatty acids involves a desaturation reaction, whereby a double bond is introduced into the fatty acyl chain. For example, in humans, the desaturation of stearic acid by stearoyl-CoA desaturase-1 produces oleic acid. The doubly unsaturated fatty acid linoleic acid as well as the triply unsaturated α-linolenic acid cannot be synthesized in mammalian tissues, and are therefore essential fatty acids and must be obtained from the diet.

Triglyceride synthesis takes place in the endoplasmic reticulum by metabolic pathways in which acyl groups in fatty acyl-CoAs are transferred to the hydroxyl groups of glycerol-3-phosphate and diacylglycerol.

Terpenes and isoprenoids, including the carotenoids, are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate. These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA, while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates. One important reaction that uses these activated isoprene donors is steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol. Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.

Degradation

Beta oxidation is the metabolic process by which fatty acids are broken down in the mitochondria or in peroxisomes to generate acetyl-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 of dehydrogenation, hydration, and oxidation to form a beta-keto acid, which is split by thiolysis. The acetyl-CoA is then ultimately converted into ATP, CO₂, and H₂O using the citric acid cycle and the electron 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. Unsaturated and odd-chain fatty acids require additional enzymatic steps for degradation.

Nutrition and health

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, and K) and carotenoids. Humans and other mammals have a dietary requirement for certain essential fatty acids, such as linoleic acid (an omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid) because they cannot be synthesized from simple precursors in the diet. Both of these fatty acids are 18-carbon polyunsaturated fatty acids differing in the number and position of the double bonds. Most vegetable oils are rich in linoleic acid (safflower, sunflower, and corn oils). Alpha-linolenic acid is found in the green leaves of plants, and in selected seeds, nuts, and legumes (in particular flax, rapeseed, walnut, and soy). Fish oils are particularly rich in the longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 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. In contrast, it is now well-established that consumption of trans fats, such as those present in partially hydrogenated vegetable oils, are a risk factor for cardiovascular disease. Fats that are good for you can be turned into trans fats by overcooking.

A few studies have suggested that total dietary fat intake is linked to an increased risk of obesity and diabetes. However, a number of very large studies, 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. 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, a website maintained by the Department of Nutrition at the Harvard School of Public Health, summarizes the current evidence on the impact 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."