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3.4: Lipids - Biology

3.4: Lipids - Biology


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What you’ll learn to do: Illustrate different types of lipids and relate their structure to their role in biological systems

Fats and oils are probably the type of lipid that you’re most familiar with in your everyday life. The word fat typically brings up a negative picture in our minds. There are also other lipids essential to human life, including phospholipids, steroids, and waxes.

While an excess of any substance can be a problem, all of these lipids play essential roles in living things.

In this outcome, we will discuss lipids and the role they plan in our bodies.

Learning Objectives

  • Distinguish between the different kinds of lipids
  • Identify several major functions of lipids

Lipids include a diverse group of compounds that are largely nonpolar in nature. This is because they are hydrocarbons that include mostly nonpolar carbon–carbon or carbon–hydrogen bonds. Non-polar molecules are hydrophobic (“water fearing”), or insoluble in water. Lipids perform many different functions in a cell. Cells store energy for long-term use in the form of fats. Lipids also provide insulation from the environment for plants and animals (Figure 1). For example, they help keep aquatic birds and mammals dry when forming a protective layer over fur or feathers because of their water-repellant hydrophobic nature. Lipids are also the building blocks of many hormones and are an important constituent of all cellular membranes. Lipids include fats, oils, waxes, phospholipids, and steroids.

Fats and Oils

A fat molecule, such as a triglyceride, consists of two main components—glycerol and fatty acids. Glycerol is an organic compound with three carbon atoms, five hydrogen atoms, and three hydroxyl (–OH) groups. Fatty acids have a long chain of hydrocarbons to which an acidic carboxyl group is attached, hence the name “fatty acid.” The number of carbons in the fatty acid may range from 4 to 36; most common are those containing 12–18 carbons. In a fat molecule, a fatty acid is attached to each of the three oxygen atoms in the –OH groups of the glycerol molecule with a covalent bond (Figure 2).

During this covalent bond formation, three water molecules are released. The three fatty acids in the fat may be similar or dissimilar. These fats are also called triglycerides because they have three fatty acids. Some fatty acids have common names that specify their origin. For example, palmitic acid, a saturated fatty acid, is derived from the palm tree. Arachidic acid is derived from Arachis hypogaea, the scientific name for peanuts.

Fatty acids may be saturated or unsaturated. In a fatty acid chain, if there are only single bonds between neighboring carbons in the hydrocarbon chain, the fatty acid is saturated. Saturated fatty acids are saturated with hydrogen; in other words, the number of hydrogen atoms attached to the carbon skeleton is maximized.

When the hydrocarbon chain contains a double bond, the fatty acid is an unsaturated fatty acid.

Most unsaturated fats are liquid at room temperature and are called oils. If there is one double bond in the molecule, then it is known as a monounsaturated fat (e.g., olive oil), and if there is more than one double bond, then it is known as a polyunsaturated fat (e.g., canola oil).

Saturated fats tend to get packed tightly and are solid at room temperature. Animal fats with stearic acid and palmitic acid contained in meat, and the fat with butyric acid contained in butter, are examples of saturated fats. Mammals store fats in specialized cells called adipocytes, where globules of fat occupy most of the cell. In plants, fat or oil is stored in seeds and is used as a source of energy during embryonic development.

Unsaturated fats or oils are usually of plant origin and contain unsaturated fatty acids. The double bond causes a bend or a “kink” that prevents the fatty acids from packing tightly, keeping them liquid at room temperature. Olive oil, corn oil, canola oil, and cod liver oil are examples of unsaturated fats. Unsaturated fats help to improve blood cholesterol levels, whereas saturated fats contribute to plaque formation in the arteries, which increases the risk of a heart attack.

Margarine, some types of peanut butter, and shortening are examples of artificially hydrogenated trans-fats. Recent studies have shown that an increase in trans-fats in the human diet may lead to an increase in levels of low-density lipoprotein (LDL), or “bad” cholesterol, which, in turn, may lead to plaque deposition in the arteries, resulting in heart disease. Many fast food restaurants have recently eliminated the use of trans-fats, and U.S. food labels are now required to list their trans-fat content.In the food industry, oils are artificially hydrogenated to make them semi-solid, leading to less spoilage and increased shelf life. Simply speaking, hydrogen gas is bubbled through oils to solidify them. During this hydrogenation process, double bonds of the cis-conformation in the hydrocarbon chain may be converted to double bonds in the trans-conformation. This forms a trans-fat from a cis-fat. The orientation of the double bonds affects the chemical properties of the fat (Figure 3).

Essential fatty acids are fatty acids that are required but not synthesized by the human body. Consequently, they must be supplemented through the diet. Omega-3 fatty acids fall into this category and are one of only two known essential fatty acids for humans (the other being omega-6 fatty acids). They are a type of polyunsaturated fat and are called omega-3 fatty acids because the third carbon from the end of the fatty acid participates in a double bond.

Salmon, trout, and tuna are good sources of omega-3 fatty acids. Omega-3 fatty acids are important in brain function and normal growth and development. They may also prevent heart disease and reduce the risk of cancer.

Like carbohydrates, fats have received a lot of bad publicity. It is true that eating an excess of fried foods and other “fatty” foods leads to weight gain. However, fats do have important functions. Fats serve as long-term energy storage. They also provide insulation for the body. Therefore, “healthy” unsaturated fats in moderate amounts should be consumed on a regular basis.

Phospholipids

Phospholipids are the major constituent of the plasma membrane. Like fats, they are composed of fatty acid chains attached to a glycerol or similar backbone. Instead of three fatty acids attached, however, there are two fatty acids and the third carbon of the glycerol backbone is bound to a phosphate group. The phosphate group is modified by the addition of an alcohol.

A phospholipid has both hydrophobic and hydrophilic regions. The fatty acid chains are hydrophobic and exclude themselves from water, whereas the phosphate is hydrophilic and interacts with water.

Cells are surrounded by a membrane, which has a bilayer of phospholipids. The fatty acids of phospholipids face inside, away from water, whereas the phosphate group can face either the outside environment or the inside of the cell, which are both aqueous.

Steroids and Waxes

Unlike the phospholipids and fats discussed earlier, steroids have a ring structure. Although they do not resemble other lipids, they are grouped with them because they are also hydrophobic. All steroids have four, linked carbon rings and several of them, like cholesterol, have a short tail.

Cholesterol is a steroid. Cholesterol is mainly synthesized in the liver and is the precursor of many steroid hormones, such as testosterone and estradiol. It is also the precursor of vitamins E and K. Cholesterol is the precursor of bile salts, which help in the breakdown of fats and their subsequent absorption by cells. Although cholesterol is often spoken of in negative terms, it is necessary for the proper functioning of the body. It is a key component of the plasma membranes of animal cells.

Waxes are made up of a hydrocarbon chain with an alcohol (–OH) group and a fatty acid. Examples of animal waxes include beeswax and lanolin. Plants also have waxes, such as the coating on their leaves, that helps prevent them from drying out.

For an additional perspective on lipids, explore this interactive animation.

Learning Objectives

Lipids are a class of macromolecules that are nonpolar and hydrophobic in nature. Major types include fats and oils, waxes, phospholipids, and steroids. Fats are a stored form of energy and are also known as triacylglycerols or triglycerides. Fats are made up of fatty acids and either glycerol or sphingosine. Fatty acids may be unsaturated or saturated, depending on the presence or absence of double bonds in the hydrocarbon chain. If only single bonds are present, they are known as saturated fatty acids. Unsaturated fatty acids may have one or more double bonds in the hydrocarbon chain. Phospholipids make up the matrix of membranes. They have a glycerol or sphingosine backbone to which two fatty acid chains and a phosphate-containing group are attached. Steroids are another class of lipids. Their basic structure has four fused carbon rings. Cholesterol is a type of steroid and is an important constituent of the plasma membrane, where it helps to maintain the fluid nature of the membrane. It is also the precursor of steroid hormones such as testosterone.

Check Your Understanding

Answer the question(s) below to see how well you understand the topics covered in the previous section. This short quiz does not count toward your grade in the class, and you can retake it an unlimited number of times.

Use this quiz to check your understanding and decide whether to (1) study the previous section further or (2) move on to the next section.


3.4: Membranes and Membrane Lipids

All living cells are surrounded by a cell membrane. Plant cells (Figure (PageIndex<1A>)) and animal cells (Figure (PageIndex<1B>)) contain a cell nucleus that is also surrounded by a membrane and holds the genetic information for the cell. Everything between the cell membrane and the nuclear membrane&mdashincluding intracellular fluids and various subcellular components such as the mitochondria and ribosomes&mdashis called the cytoplasm. The membranes of all cells have a fundamentally similar structure, but membrane function varies tremendously from one organism to another and even from one cell to another within a single organism. This diversity arises mainly from the presence of different proteins and lipids in the membrane.

Figure (PageIndex<1>): (A) An Idealized Plant Cell. Not all the structures shown here occur in every type of plant cell. (B) An Idealized Animal Cell. The structures shown here will seldom all be found in a single animal cell.

The lipids in cell membranes are highly polar but have dual characteristics: part of the lipid is ionic and therefore dissolves in water, whereas the rest has a hydrocarbon structure and therefore dissolves in nonpolar substances. Often, the ionic part is referred to as hydrophilic, meaning &ldquowater loving,&rdquo and the nonpolar part as hydrophobic, meaning &ldquowater fearing&rdquo (repelled by water). When allowed to float freely in water, polar lipids spontaneously cluster together in any one of three arrangements: micelles, monolayers, and bilayers (Figure (PageIndex<2>)).

Figure (PageIndex<2>): Spontaneously Formed Polar Lipid Structures in Water: Monolayer, Micelle, and Bilayer

Micelles are aggregations in which the lipids&rsquo hydrocarbon tails&mdashbeing hydrophobic&mdashare directed toward the center of the assemblage and away from the surrounding water while the hydrophilic heads are directed outward, in contact with the water. Each micelle may contain thousands of lipid molecules. Polar lipids may also form a monolayer, a layer one molecule thick on the surface of the water. The polar heads face into water, and the nonpolar tails stick up into the air. Bilayers are double layers of lipids arranged so that the hydrophobic tails are sandwiched between an inner surface and an outer surface consisting of hydrophilic heads. The hydrophilic heads are in contact with water on either side of the bilayer, whereas the tails, sequestered inside the bilayer, are prevented from having contact with the water. Bilayers like this make up every cell membrane (Figure (PageIndex<3>)).

Figure (PageIndex<3>): Schematic Diagram of a Cell Membrane. The membrane enclosing a typical animal cell is a phospholipid bilayer with embedded cholesterol and protein molecules. Short oligosaccharide chains are attached to the outer surface.

In the bilayer interior, the hydrophobic tails (that is, the fatty acid portions of lipid molecules) interact by means of dispersion forces. The interactions are weakened by the presence of unsaturated fatty acids. As a result, the membrane components are free to mill about to some extent, and the membrane is described as fluid.

The lipids found in cell membranes can be categorized in various ways. Phospholipids are lipids containing phosphorus. Glycolipids are sugar-containing lipids. The latter are found exclusively on the outer surface of the cell membrane, acting as distinguishing surface markers for the cell and thus serving in cellular recognition and cell-to-cell communication. Sphingolipids are phospholipids or glycolipids that contain the unsaturated amino alcohol sphingosine rather than glycerol. Diagrammatic structures of representative membrane lipids are presented in Figure (PageIndex<4>).

Figure (PageIndex<4>): Component Structures of Some Important Membrane Lipids

Phosphoglycerides (also known as glycerophospholipids) are the most abundant phospholipids in cell membranes. They consist of a glycerol unit with fatty acids attached to the first two carbon atoms, while a phosphoric acid unit, esterified with an alcohol molecule (usually an amino alcohol, as in part (a) of Figure (PageIndex<5>)) is attached to the third carbon atom of glycerol (part (b) of Figure (PageIndex<5>)). Notice that the phosphoglyceride molecule is identical to a triglyceride up to the phosphoric acid unit (part (b) of Figure (PageIndex<5>)).

Figure (PageIndex<5>): Phosphoglycerides. (a) Amino alcohols are commonly found in phosphoglycerides, which are evident in its structural formula (b).

There are two common types of phosphoglycerides. Phosphoglycerides containing ethanolamine as the amino alcohol are called phosphatidylethanolamines or cephalins. Cephalins are found in brain tissue and nerves and also have a role in blood clotting. Phosphoglycerides containing choline as the amino alcohol unit are called phosphatidylcholines or lecithins. Lecithins occur in all living organisms. Like cephalins, they are important constituents of nerve and brain tissue. Egg yolks are especially rich in lecithins. Commercial-grade lecithins isolated from soybeans are widely used in foods as emulsifying agents. An emulsifying agent is used to stabilize an emulsion &mdasha dispersion of two liquids that do not normally mix, such as oil and water. Many foods are emulsions. Milk is an emulsion of butterfat in water. The emulsifying agent in milk is a protein called casein. Mayonnaise is an emulsion of salad oil in water, stabilized by lecithins present in egg yolk.

Sphingomyelins , the simplest sphingolipids, each contain a fatty acid, a phosphoric acid, sphingosine, and choline (Figure (PageIndex<6>)). Because they contain phosphoric acid, they are also classified as phospholipids. Sphingomyelins are important constituents of the myelin sheath surrounding the axon of a nerve cell. Multiple sclerosis is one of several diseases resulting from damage to the myelin sheath.

Figure (PageIndex<6>): Sphingolipids. (a) Sphingosine, an amino alcohol, is found in all sphingolipids. (b) A sphingomyelin is also known as a phospholipid, as evidenced by the phosphoric acid unit in its structure.

Most animal cells contain sphingolipids called cerebrosides (Figure (PageIndex<7>)). Cerebrosides are composed of sphingosine, a fatty acid, and galactose or glucose. They therefore resemble sphingomyelins but have a sugar unit in place of the choline phosphate group. Cerebrosides are important constituents of the membranes of nerve and brain cells.

Figure (PageIndex<7>): Cerebrosides. Cerebrosides are sphingolipids that contain a sugar unit.

The sphingolipids called gangliosides are more complex, usually containing a branched chain of three to eight monosaccharides and/or substituted sugars. Because of considerable variation in their sugar components, about 130 varieties of gangliosides have been identified. Most cell-to-cell recognition and communication processes (e.g., blood group antigens) depend on differences in the sequences of sugars in these compounds. Gangliosides are most prevalent in the outer membranes of nerve cells, although they also occur in smaller quantities in the outer membranes of most other cells. Because cerebrosides and gangliosides contain sugar groups, they are also classified as glycolipids.


3.3 Lipids

In this section, you will explore the following questions:

  • What are the four major types of lipids?
  • What are functions of fats in living organisms?
  • What is the difference between saturated and unsaturated fatty acids?
  • What is the molecular structure of phospholipids, and what is the role of phospholipids in cells?
  • What is the basic structure of a steroid, and what are examples of their functions?
  • How does cholesterol help maintain the fluid nature of the plasma membrane of cells?

Connection for AP ® Courses

Lipids also are sources of energy that power cellular processes. Like carbohydrates, lipids are composed of carbon, hydrogen, and oxygen, but these atoms are arranged differently. Most lipids are nonpolar and hydrophobic. Major types include fats and oils, waxes, phospholipids, and steroids. A typical fat consists of three fatty acids bonded to one molecule of glycerol, forming triglycerides or triacylglycerols. The fatty acids may be saturated or unsaturated, depending on the presence or absence of double bonds in the hydrocarbon chain a saturated fatty acid has the maximum number of hydrogen atoms bonded to carbon and, thus, only single bonds. In general, fats that are liquid at room temperature (e.g., canola oil) tend to be more unsaturated than fats that are solid at room temperature. In the food industry, oils are artificially hydrogenated to make them chemically more appropriate for use in processed foods. During this hydrogenation process, double bonds in the cis- conformation in the hydrocarbon chain may be converted to double bonds in the trans- conformation unfortunately, trans fats have been shown to contribute to heart disease. Phospholipids are a special type of lipid associated with cell membranes and typically have a glycerol (or sphingosine) backbone to which two fatty acid chains and a phosphate-containing group are attached. As a result, phospholipids are considered amphipathic because they have both hydrophobic and hydrophilic components. (In Chapters 4 and 5 we will explore in more detail how the amphipathic nature of phospholipids in plasma cell membranes helps regulate the passage of substances into and out of the cell.) Although the molecular structures of steroids differ from that of triglycerides and phospholipids, steroids are classified as lipids based on their hydrophobic properties. Cholesterol is a type of steroid in animal cells’ plasma membrane. Cholesterol is also the precursor of steroid hormones such as testosterone.

Information presented and the examples highlighted in the section, support concepts outlined in Big Idea 4 of the AP ® Biology Curriculum Framework. The learning objectives listed in the Curriculum Framework provide a transparent foundation for the AP ® Biology course, an inquiry-based laboratory experience, instructional activities, and AP ® exam questions. A Learning Objective merges required content with one or more of the seven Science Practices.

Big Idea 4 Biological systems interact, and these systems and their interactions possess complex properties.
Enduring Understanding 4.A Interactions within biological systems lead to complex properties.
Essential Knowledge 4.A.1 The subcomponents of biological molecules and their sequence determine the properties of that molecule.
Science Practice 7.1 The student can connect phenomena and models across spatial and temporal scales.
Learning Objective 4.1 The student is able to explain the connection between the sequence and the subcomponents of a biological polymer and its properties.
Essential Knowledge 4.A.1 The subcomponents of biological molecules and their sequence determine the properties of that molecule.
Science Practice 1.3 The student can refine representations and models of natural or man-made phenomena and systems in the domain.
Learning Objective 4.2 The student is able to refine representations and models to explain how the subcomponents of a biological polymer and their sequence determine the properties of that polymer.
Essential Knowledge 4.A.1 The subcomponents of biological molecules and their sequence determine the properties of that molecule.
Science Practice 6.1 The student can justify claims with evidence.
Science Practice 6.4 The student can make claims and predictions about natural phenomena based on scientific theories and models.
Learning Objective 4.3 The student is able to use models to predict and justify that changes in the subcomponents of a biological polymer affect the functionality of the molecules.

Teacher Support

An important misconception to overcome for students is that lipids are not bad for the body. They are absolutely essential to the body’s functions, including for growth and survival.

Another concept to discuss is the insolubility of lipids in water. It is obvious in salad dressing, but why does it occur? If other functional groups are attached to lipids, they may contain some charges and give a degree of solubility to the lipid, but most lipids do not have any charges on the surface of the molecules and are not soluble in water, therefore, lipids are usually described as being hydrophobic.

Insoluble lipids must be attached to proteins in the body to become soluble in body fluids. Have the class research the proteins that transport and carry lipids. Identify their contributions to health or sickness.

The Science Practice Challenge Questions contain additional test questions for this section that will help you prepare for the AP exam. These questions address the following standards:
[APLO 2.9] [APLO 2.10] [APLO 2.12] [APLO 2.13][APLO 2.14][APLO 4.14]

Fats and Oils

Lipids include a diverse group of compounds that are largely nonpolar in nature. This is because they are hydrocarbons that include mostly nonpolar carbon–carbon or carbon–hydrogen bonds. Non-polar molecules are hydrophobic (“water fearing”), or insoluble in water. Lipids perform many different functions in a cell. Cells store energy for long-term use in the form of fats. Lipids also provide insulation from the environment for plants and animals (Figure 3.13). For example, their water-repellant hydrophobic nature can help keep aquatic birds and mammals dry by forming a protective layer over fur or feathers. Lipids are also the building blocks of many hormones and an important constituent of all cellular membranes. Lipids include fats, waxes, phospholipids, and steroids.

Teacher Support

The difference between a fat and an oil is the state of the compound at room temperature (68°F). A fat is a solid or semisolid material and an oil is a liquid at this temperature. Both fats and oils are made up of glycerol and two or three fatty acid chains attached to its carbons by way of dehydration synthesis. A fatty acid is a chain of carbon atoms with hydrogen atoms attached at the open bonding sites. If the chain is fully saturated with hydrogen atoms, it is termed a saturated fat. This tends to give the compound a relatively stiff configuration and helps it to be a solid. If any of the hydrogen atoms are missing, it is called an unsaturated fat or oil. The absence of hydrogen atoms along the chain causes double bonds to form between adjacent carbon atoms, which results in a bend in the chain. This causes the molecules to push away other molecules near it, preventing the packing of fatty acid chains, and resulting in a liquid at room temperature. Fats tend to contain a high concentration of saturated fatty acids and oils tend to contain more unsaturated fatty acid chains. Both types have an effect on health a high amount of saturated fats is significantly less healthy than a higher amount of unsaturated lipids. An exception trans fat, an unsaturated fat found in processed foods. Trans fats behave like a saturated lipid.

Divide the class into three sections: section 1: dairy department section 2: salad dressings, and section 3: potato chips.. Each section will visit the supermarket and identify which fats or oils are in five items in their category. Then, each section will prepare a chart listing their findings and share it with the class.

A fat molecule consists of two main components—glycerol and fatty acids. Glycerol is an organic compound (alcohol) with three carbons, five hydrogens, and three hydroxyl (OH) groups. Fatty acids have a long chain of hydrocarbons to which a carboxyl group is attached, hence the name “fatty acid.” The number of carbons in the fatty acid may range from 4 to 36 most common are those containing 12–18 carbons. In a fat molecule, the fatty acids are attached to each of the three carbons of the glycerol molecule with an ester bond through an oxygen atom (Figure 3.14).

During this ester bond formation, three water molecules are released. The three fatty acids in the triacylglycerol may be similar or dissimilar. Fats are also called triacylglycerols or triglycerides because of their chemical structure. Some fatty acids have common names that specify their origin. For example, palmitic acid, a saturated fatty acid , is derived from the palm tree. Arachidic acid is derived from Arachis hypogea, the scientific name for groundnuts or peanuts.

Fatty acids may be saturated or unsaturated. In a fatty acid chain, if there are only single bonds between neighboring carbons in the hydrocarbon chain, the fatty acid is said to be saturated. Saturated fatty acids are saturated with hydrogen in other words, the number of hydrogen atoms attached to the carbon skeleton is maximized. Stearic acid is an example of a saturated fatty acid (Figure 3.15)

When the hydrocarbon chain contains a double bond, the fatty acid is said to be unsaturated . Oleic acid is an example of an unsaturated fatty acid (Figure 3.16).

Most unsaturated fats are liquid at room temperature and are called oils. If there is one double bond in the molecule, then it is known as a monounsaturated fat (e.g., olive oil), and if there is more than one double bond, then it is known as a polyunsaturated fat (e.g., canola oil).

When a fatty acid has no double bonds, it is known as a saturated fatty acid because no more hydrogen may be added to the carbon atoms of the chain. A fat may contain similar or different fatty acids attached to glycerol. Long straight fatty acids with single bonds tend to get packed tightly and are solid at room temperature. Animal fats with stearic acid and palmitic acid (common in meat) and the fat with butyric acid (common in butter) are examples of saturated fats. Mammals store fats in specialized cells called adipocytes, where globules of fat occupy most of the cell’s volume. In plants, fat or oil is stored in many seeds and is used as a source of energy during seedling development. Unsaturated fats or oils are usually of plant origin and contain cis unsaturated fatty acids. Cis and trans indicate the configuration of the molecule around the double bond. If hydrogens are present in the same plane, it is referred to as a cis fat if the hydrogen atoms are on two different planes, it is referred to as a trans fat . The cis double bond causes a bend or a “kink” that prevents the fatty acids from packing tightly, keeping them liquid at room temperature (Figure 3.17). Olive oil, corn oil, canola oil, and cod liver oil are examples of unsaturated fats. Unsaturated fats help to lower blood cholesterol levels whereas saturated fats contribute to plaque formation in the arteries.

Trans Fats

In the food industry, oils are artificially hydrogenated to make them semi-solid and of a consistency desirable for many processed food products. Simply speaking, hydrogen gas is bubbled through oils to solidify them. During this hydrogenation process, double bonds of the cis- conformation in the hydrocarbon chain may be converted to double bonds in the trans- conformation.

Margarine, some types of peanut butter, and shortening are examples of artificially hydrogenated trans fats. Recent studies have shown that an increase in trans fats in the human diet may lead to an increase in levels of low-density lipoproteins (LDL), or “bad” cholesterol, which in turn may lead to plaque deposition in the arteries, resulting in heart disease. Many fast food restaurants have recently banned the use of trans fats, and food labels are required to display the trans fat content.

Omega Fatty Acids

Essential fatty acids are fatty acids required but not synthesized by the human body. Consequently, they have to be supplemented through ingestion via the diet. Omega -3 fatty acids (like that shown in Figure 3.18) fall into this category and are one of only two known for humans (the other being omega-6 fatty acid). These are polyunsaturated fatty acids and are called omega-3 because the third carbon from the end of the hydrocarbon chain is connected to its neighboring carbon by a double bond.

The farthest carbon away from the carboxyl group is numbered as the omega (ω) carbon, and if the double bond is between the third and fourth carbon from that end, it is known as an omega-3 fatty acid. Nutritionally important because the body does not make them, omega-3 fatty acids include alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated. Salmon, trout, and tuna are good sources of omega-3 fatty acids. Research indicates that omega-3 fatty acids reduce the risk of sudden death from heart attacks, reduce triglycerides in the blood, lower blood pressure, and prevent thrombosis by inhibiting blood clotting. They also reduce inflammation, and may help reduce the risk of some cancers in animals.

Like carbohydrates, fats have received a lot of bad publicity. It is true that eating an excess of fried foods and other “fatty” foods leads to weight gain. However, fats do have important functions. Many vitamins are fat soluble, and fats serve as a long-term storage form of fatty acids: a source of energy. They also provide insulation for the body. Therefore, “healthy” fats in moderate amounts should be consumed on a regular basis.

Teacher Support

This question is an application Learning Objective 4.3 and Science Practices 6.1 and 6.4 because students are predicting how a change in the subcomponents of a molecule can affect the properties of the molecule.

A phospholipid is made of a phosphate group bonded to a glycerol that is linked to two fatty acid chains. One of the fatty acid chains is saturated and the other unsaturated. The saturated one is straight, while the unsaturated chain contains a bend. Phospholipids make up lipid bilayers, the main component of most plasma membranes and give it a fluid like property, a result of the fatty acid tails creating space between phospholipid molecules.

The concept of a bent fatty acid tail contributing to the fluidity of a cell membrane can be difficult to visualize. Obtain some old fashioned, wooden clothes-pins. The knob at the top becomes a phosphate molecule. The two prongs of the pins become fatty acids. Both prongs are stiff, so they are saturated fatty acids. There are no unsaturated fatty acids in this demonstration. Hold a number of the pins tightly in your hand and ask a student to remove a pin in the center. They shouldn’t be able to, as you are pressing the prongs of all of the pins together. This would be in a cell membrane without any unsaturated fatty acids pushing adjacent chains away, creating spaces that allow the membrane to behave like a fluid.


3.3 Lipids

Lipids include a diverse group of compounds that are largely nonpolar in nature. This is because they are hydrocarbons that include mostly nonpolar carbon–carbon or carbon–hydrogen bonds. Non-polar molecules are hydrophobic (“water fearing”), or insoluble in water. Lipids perform many different functions in a cell. Cells store energy for long-term use in the form of fats. Lipids also provide insulation from the environment for plants and animals (Figure 3.12). For example, they help keep aquatic birds and mammals dry when forming a protective layer over fur or feathers because of their water-repellant hydrophobic nature. Lipids are also the building blocks of many hormones and are an important constituent of all cellular membranes. Lipids include fats, oils, waxes, phospholipids, and steroids.

Fats and Oils

A fat molecule consists of two main components—glycerol and fatty acids. Glycerol is an organic compound (alcohol) with three carbons, five hydrogens, and three hydroxyl (OH) groups. Fatty acids have a long chain of hydrocarbons to which a carboxyl group is attached, hence the name “fatty acid.” The number of carbons in the fatty acid may range from 4 to 36 most common are those containing 12–18 carbons. In a fat molecule, the fatty acids are attached to each of the three carbons of the glycerol molecule with an ester bond through an oxygen atom (Figure 3.13).

During this ester bond formation, three water molecules are released. The three fatty acids in the triacylglycerol may be similar or dissimilar. Fats are also called triacylglycerols or triglycerides because of their chemical structure. Some fatty acids have common names that specify their origin. For example, palmitic acid, a saturated fatty acid , is derived from the palm tree. Arachidic acid is derived from Arachis hypogea, the scientific name for groundnuts or peanuts.

Fatty acids may be saturated or unsaturated. In a fatty acid chain, if there are only single bonds between neighboring carbons in the hydrocarbon chain, the fatty acid is said to be saturated. Saturated fatty acids are saturated with hydrogen in other words, the number of hydrogen atoms attached to the carbon skeleton is maximized. Stearic acid is an example of a saturated fatty acid (Figure 3.14)

When the hydrocarbon chain contains a double bond, the fatty acid is said to be unsaturated . Oleic acid is an example of an unsaturated fatty acid (Figure 3.15).

Most unsaturated fats are liquid at room temperature and are called oils. If there is one double bond in the molecule, then it is known as a monounsaturated fat (e.g., olive oil), and if there is more than one double bond, then it is known as a polyunsaturated fat (e.g., canola oil).

When a fatty acid has no double bonds, it is known as a saturated fatty acid because no more hydrogen may be added to the carbon atoms of the chain. A fat may contain similar or different fatty acids attached to glycerol. Long straight fatty acids with single bonds tend to get packed tightly and are solid at room temperature. Animal fats with stearic acid and palmitic acid (common in meat) and the fat with butyric acid (common in butter) are examples of saturated fats. Mammals store fats in specialized cells called adipocytes, where globules of fat occupy most of the cell’s volume. In plants, fat or oil is stored in many seeds and is used as a source of energy during seedling development. Unsaturated fats or oils are usually of plant origin and contain cis unsaturated fatty acids. Cis and trans indicate the configuration of the molecule around the double bond. If hydrogens are present in the same plane, it is referred to as a cis fat if the hydrogen atoms are on two different planes, it is referred to as a trans fat . The cis double bond causes a bend or a “kink” that prevents the fatty acids from packing tightly, keeping them liquid at room temperature (Figure 3.16). Olive oil, corn oil, canola oil, and cod liver oil are examples of unsaturated fats. Unsaturated fats help to lower blood cholesterol levels whereas saturated fats contribute to plaque formation in the arteries.

Trans Fats

In the food industry, oils are artificially hydrogenated to make them semi-solid and of a consistency desirable for many processed food products. Simply speaking, hydrogen gas is bubbled through oils to solidify them. During this hydrogenation process, double bonds of the cis- conformation in the hydrocarbon chain may be converted to double bonds in the trans- conformation.

Margarine, some types of peanut butter, and shortening are examples of artificially hydrogenated trans fats. Recent studies have shown that an increase in trans fats in the human diet may lead to an increase in levels of low-density lipoproteins (LDL), or “bad” cholesterol, which in turn may lead to plaque deposition in the arteries, resulting in heart disease. Many fast food restaurants have recently banned the use of trans fats, and food labels are required to display the trans fat content.

Omega Fatty Acids

Essential fatty acids are fatty acids required but not synthesized by the human body. Consequently, they have to be supplemented through ingestion via the diet. Omega -3 fatty acids (like that shown in Figure 3.17) fall into this category and are one of only two known for humans (the other being omega-6 fatty acid). These are polyunsaturated fatty acids and are called omega-3 because the third carbon from the end of the hydrocarbon chain is connected to its neighboring carbon by a double bond.

The farthest carbon away from the carboxyl group is numbered as the omega (ω) carbon, and if the double bond is between the third and fourth carbon from that end, it is known as an omega-3 fatty acid. Nutritionally important because the body does not make them, omega-3 fatty acids include alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated. Salmon, trout, and tuna are good sources of omega-3 fatty acids. Research indicates that omega-3 fatty acids reduce the risk of sudden death from heart attacks, reduce triglycerides in the blood, lower blood pressure, and prevent thrombosis by inhibiting blood clotting. They also reduce inflammation, and may help reduce the risk of some cancers in animals.

Like carbohydrates, fats have received a lot of bad publicity. It is true that eating an excess of fried foods and other “fatty” foods leads to weight gain. However, fats do have important functions. Many vitamins are fat soluble, and fats serve as a long-term storage form of fatty acids: a source of energy. They also provide insulation for the body. Therefore, “healthy” fats in moderate amounts should be consumed on a regular basis.

Waxes

Wax covers the feathers of some aquatic birds and the leaf surfaces of some plants. Because of the hydrophobic nature of waxes, they prevent water from sticking on the surface (Figure 3.18). Waxes are made up of long fatty acid chains esterified to long-chain alcohols.

Phospholipids

Phospholipids are major constituents of the plasma membrane, the outermost layer of animal cells. Like fats, they are composed of fatty acid chains attached to a glycerol or sphingosine backbone. Instead of three fatty acids attached as in triglycerides, however, there are two fatty acids forming diacylglycerol, and the third carbon of the glycerol backbone is occupied by a modified phosphate group (Figure 3.19). A phosphate group alone attached to a diaglycerol does not qualify as a phospholipid it is phosphatidate (diacylglycerol 3-phosphate), the precursor of phospholipids. The phosphate group is modified by an alcohol. Phosphatidylcholine and phosphatidylserine are two important phospholipids that are found in plasma membranes.

A phospholipid is an amphipathic molecule, meaning it has a hydrophobic and a hydrophilic part. The fatty acid chains are hydrophobic and cannot interact with water, whereas the phosphate-containing group is hydrophilic and interacts with water (Figure 3.20).

The head is the hydrophilic part, and the tail contains the hydrophobic fatty acids. In a membrane, a bilayer of phospholipids forms the matrix of the structure, the fatty acid tails of phospholipids face inside, away from water, whereas the phosphate group faces the outside, aqueous side (Figure 3.20).

Phospholipids are responsible for the dynamic nature of the plasma membrane. If a drop of phospholipids is placed in water, it spontaneously forms a structure known as a micelle, where the hydrophilic phosphate heads face the outside and the fatty acids face the interior of this structure.

Steroids

Unlike the phospholipids and fats discussed earlier, steroids have a fused ring structure. Although they do not resemble the other lipids, they are grouped with them because they are also hydrophobic and insoluble in water. All steroids have four linked carbon rings and several of them, like cholesterol, have a short tail (Figure 3.21). Many steroids also have the –OH functional group, which puts them in the alcohol classification (sterols).

Cholesterol is the most common steroid. Cholesterol is mainly synthesized in the liver and is the precursor to many steroid hormones such as testosterone and estradiol, which are secreted by the gonads and endocrine glands. It is also the precursor to Vitamin D. Cholesterol is also the precursor of bile salts, which help in the emulsification of fats and their subsequent absorption by cells. Although cholesterol is often spoken of in negative terms by lay people, it is necessary for proper functioning of the body. It is a component of the plasma membrane of animal cells and is found within the phospholipid bilayer. Being the outermost structure in animal cells, the plasma membrane is responsible for the transport of materials and cellular recognition and it is involved in cell-to-cell communication.

Link to Learning

For an additional perspective on lipids, explore the interactive animation “Biomolecules: The Lipids”


In 1988, Lewis C. Cantley published a paper describing the discovery of a novel type of phosphoinositide kinase with the unprecedented ability to phosphorylate the 3' position of the inositol ring resulting in the formation of phosphatidylinositol-3-phosphate (PI3P). [1] Working independently, Alexis Traynor-Kaplan and coworkers published a paper demonstrating that a novel lipid, phosphatidylinositol 3,4,5 trisphosphate (PIP3) occurs naturally in human neutrophils with levels that increased rapidly following physiologic stimulation with chemotactic peptide. [2] Subsequent studies demonstrated that in vivo the enzyme originally identified by Cantley's group prefers PtdIns(4,5)P2 as a substrate, producing the product PIP3. [3]

PIP3 functions to activate downstream signaling components, the most notable one being the protein kinase AKT, which activates downstream anabolic signaling pathways required for cell growth and survival. [4]

PtdIns(3,4,5)P3 is dephosphorylated by the phosphatase PTEN on the 3 position, generating PI(4,5)P2, and by SHIPs (SH2-containing inositol phosphatase) on the 5' position of the inositol ring, producing PI(3,4)P2. [5]

The PH domain in a number of proteins binds to PtdIns(3,4,5)P3. Such proteins include Akt/PKB, [6] PDK1, [7] Btk1, and ARNO. [8]

PIP3 continues to play a critical role outside of the cytosol, notably at the postsynaptic terminal of hippocampal cells. Here, PIP3 has been implicated in regulating synaptic strengthening and AMPA expression, contributing to long-term potentiation. Moreover, PIP3 suppression disrupts normal AMPA expression on the neuron membrane and instead leads to the accumulation of AMPA on dendritic spines, commonly associated with synaptic depression. [9]

Although clearly an important molecule alone, it is notable that PIP3 interacts with other proteins to mediate synaptic plasticity. Of these proteins, Phldb2 has been shown to interact with PIP3 to induce and maintain LTP. In the absence of such an interaction, memory consolidation is impaired. [10]


Phosphatidylinositol 3,4-bisphosphate

Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2) is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways. [1]

Of all the phospholipids found within the membrane, inositol phospholipids make up less than 10%. [2] Phosphoinositide’s (PI’s) also known as phosphatidylinositol phosphates, are synthesized in the cells endoplasmic reticulum by the protein phosphatidylinositol synthase (PIS). [3] [4] [5] PI’s are highly compartmentalized, their main components include a glycerol backbone, two fatty acid chains enriched with stearic acid and arachidonic acid, and an inositol ring whose phosphate groups regulation differs between organelles depending on the specific PI and PIP kinases and PIP phosphatases present in the organelle (Image 1). [6] [7] [8] These kinases and phosphatases conduct phosphorylation and dephosphorylation at the inositol sugar head groups 3’, 4’, and 5’ positions, producing differing phosphoinositides, including PtdIns(3,4)P2 (Image 2). [9] [1] PI kinases catalyze phosphate groups binding while PI phosphatases remove phosphate groups at the three positions on the PI inositol ring, giving seven different combinations of PI’s. [10] [11]

PtdIns(3,4)P2 is dephophosphorylated by the phosphatase INPP4B on the 4 position of the inositol ring and by the TPTE (transmembrane phosphatases with tensin homology) family of phosphatases on the 3 position of the inositol ring.

The PH domain in a number of proteins binds to PtdIns(3,4)P2 including the PH domain in PKB. The generation of PtdIns(3,4)P2 at the plasma membrane upon the activation of class I PI 3-kinases and SHIP phosphatases causes these proteins to translocate to the plasma membrane, thereby affecting their activity.

Class I and II phosphoinositide 3-kinases (PI3Ks) synthesize PtdIns(3,4)P2 by phosphorylating the phosphoinositide PI4P’s 3-OH position. [12] [13] Phosphatases SHIP1 and SH2-containing inositol 5’-polyphosphatases (SHIP2) produce PtdIns(3,4)P2 through desphosphorylation of PtdIns(3,4,5)P3’s 5’ inositol ring position. [14] [15] In addition to these positive regulators at the plasma membrane (PM), 3-phosphatase tensin homolog (PTEN) acts as a negative regulator of PtdIns(3,4)P2 production by depleting PtdIns(3,4,5)P3 levels at the PM through dephosphorylation of PtdIns(3,4,5)P3’s 3’ inositol ring position, giving rise to PtdIns(4,5)P2. [16] [17] Inositol polyphosphate 4-phosphatase isozymes, INPP4A and INPP4B, also act as negative PtdIns(3,4)P2 regulators, though through a more direct interaction- by hydrolyzing PtdIns(3,4)P2’s 4-phosphate, producing PI3P. [18] [19] [20] PtdIns(3,4)P2 has been indicated to be critical for AKT (Protein kinase B, PKB https://en.wikipedia.org/wiki/Protein_kinase_B) activation within the PI3K pathway through the PI’s regulation by the SHIP1 and 2 phosphatases. Akt is recruited and subsequently activated through its PH domains interaction with PtdIns(3,4)P2 and PtdIns(3,4,5)P3 both of which have shown to have high affinity with the Akt PH domain. [21] Once bound to the PM through its interaction with PtdIns(3,4)P2 and PtdIns(3,4,5)P3, Akt is activated through release of its auto-inhibitory interaction between the PH and kinase domains. [22] Following this release, T308 in the proteins activation loop and S437 in the proteins hydrophobic domain are phosphorylated by Phosphoinositide-dependent kinase-1 (PDK1) [23] and mechanistic target of Rapamycin Complex 2 (mTORC2), [24] respectively. Test tube experiments have shown that the essential recruitment of PDK1 for Akt activation at the PM can be driven through interactions with both PtdIns(3,4)P2 and PtdIns(3,4,5)P3. [25]

It was originally presumed that 5-phosphatases dephosphorylation of PI(3,4,5)P3 would be anti-tumoral, similar to tumor suppressor PTEN. Yet the 5-phosphatase SHIP proteins synthesis of PI(3,4)P2 has been linked to tumor cell survival due to the lipid’s binding and subsequent activation of Akt. [26] Akt activation causes downstream metabolism alterations, apoptosis suppression and a rise in cell proliferation. [27] This pathway and its effects have shown up in 50% of cancers. [28] In conjunction, investigators have shown a rise in PI(3,4)P2 levels and mutation of 4-phosphatase INPP4B has shown mammary epithelial transformation. [29] Recently, PtdIns(3,4)P2 has been shown to play an important role in vesicle maturation during clathrin-mediated endocytosis (CME) (https://en.wikipedia.org/wiki/Receptor-mediated_endocytosis). [30] [31] PtdIns(4)P synthesizing phosphatases SHIP2 and synaptojanin are recruited to clathrin structures at the beginning of the CME process. [32] [33] This production of PtdIns(4)P subsequently leads to PtdIns(3,4)P2 synthesis through PI3K-C2α11, and the newly synthesized PtdIns(3,4)P2 then recruits SNX9 and SNX18 PX-BAR domain proteins which narrow the nascent vesicles neck to eventually be cut and released by dynamin, forming vesicles. [34] [35] PI(3,4)P2 plays another possible role at the PM, promoting cytoskeletal rearrangements through actin regulatory proteins like Lamellipodin. [36] [37] Lamellipodin is recruited to the PM where it is believed to interact with PI(3,4)P2 through its PH domain. Once at the PM, it can regulate lamellipodia actin networks and cell migration by interacting with actin-binding proteins like Ena/VASP. [38] [39] [40]

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The chemistry and biology of phosphatidylinositol 4-phosphate at the plasma membrane

Phosphoinositides are an important class of anionic, low abundance signaling lipids distributed throughout intracellular membranes. The plasma membrane contains three phosphoinositides: PI(4)P, PI(4,5)P2, and PI(3,4,5)P3. Of these, PI(4)P has remained the most mysterious, despite its characterization in this membrane more than a half-century ago. Fortunately, recent methodological innovations at the chemistry–biology interface have spurred a renaissance of interest in PI(4)P. Here, we describe these new toolsets and how they have revealed novel functions for the plasma membrane PI(4)P pool. We examine high-resolution structural characterization of the plasma membrane PI 4-kinase complex that produces PI(4)P, tools for modulating PI(4)P levels including isoform-selective PI 4-kinase inhibitors, and fluorescent probes for visualizing PI(4)P. Collectively, these chemical and biochemical approaches have revealed insights into how cells regulate synthesis of PI(4)P and its downstream metabolites as well as new roles for plasma membrane PI(4)P in non-vesicular lipid transport, membrane homeostasis and trafficking, and cell signaling pathways.


Lipids in Exosome Biology

Extracellular vesicles (EVs), and exosomes in particular, were initially considered as "garbage bags" for secretion of undesired cellular components. This view has changed considerably over the last two decades, and exosomes have now emerged as important organelles controlling cell-to-cell signaling. They are present in biological fluids and have important roles in the communication between cells in physiological and pathological processes. They are envisioned for clinical use as carriers of biomarkers, therapeutic targets, and vehicles for drug delivery. Important efforts are being made to characterize the contents of these vesicles and to understand the mechanisms that govern their biogenesis and modes of action. This chapter aims to recapitulate the place given to lipids in our understanding of exosome biology. Besides their structural role and their function as carriers, certain lipids and lipid-modifying enzymes seem to exert privileged functions in this mode of cellular communication. By extension, the use of selective "lipid inhibitors" might turn out to be interesting modulators of exosomal-based cell signaling.

Keywords: Cell signaling Ceramide Exosomes Neutral sphingomyelinase 2 Phosphatidic acid Phospholipase D2.


Author information

Affiliations

Department of Cell Biology, Yale School of Medicine, 333 Cedar Street, New Haven, 06510, Connecticut, USA

Abdou Rachid Thiam & Tobias C. Walther

Laboratoire de Physique Statistique, Ecole Normale Supérieure de Paris, Université Pierre et Marie Curie, Université Paris Diderot, Centre National de la Recherche Scientifique, 24 rue Lhomond, Paris, 75005, France

Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, 94158, California, USA

Departments of Medicine and Biochemistry and Biophysics, University of California, San Francisco, 94158, California, USA

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Corresponding authors


Lessons learned for future cancer treatment

We presented our data suggesting that not only can gene amplifications and gene mutations act as tumor drivers in addition, increased expression of PI3K regulators can also promote carcinogenesis (Ana Carrera, Centro Nacional de Biotecnología/CSIC, Spain). This is indeed the case for p85β, a regulatory component of class I PI3K proteins that is expressed at low levels in most normal cells that exhibit preferential expression of p85α (Fig. 1). p85β levels, however, increase in several tumor types and contribute to accelerate tumor progression and metastasis. Reduction of p85β levels is therapeutic in mouse-grown tumors, indicating that the increase of PIK3R2 (the gene encoding p85β) expression can act as a driver event in cancer (Vallejo-Díaz et al., 2016 Cortés et al., 2012). Detection of PI3K regulators that act as drivers in cancer might help in the stratification of PI3K-active tumors. An increase in p85β expression should be considered for the design of new therapies aimed at interfering with PI3K action.

Bart Vanhaesebroeck (UCL Cancer Institute, UK) discussed possible alternatives to the therapy protocols that are currently used with PI3K inhibitors. Given that PI3Kα-activating mutations mediate a moderate activation of the pathway, he argues that it might make more sense to treat patients with low doses of PI3K inhibitors to prevent the inactivation of the negative-feedback loops or the acquisition of resistance (Semple and Vanhaesebroeck, 2018). He also discussed the potential utility of inhibitors of PI3K isoforms expressed in hematopoietic cells for use in cancer immunotherapy for solid tumors, and how an adaptive immune response most likely also contributes to the clinical efficacy of the PI3Kδ inhibitors in B-cell malignancies.

Along the same line, Klaus Okkenhaug (University of Cambridge, UK) presented an update on the use of inhibitory compounds for PI3Kδ (an isoform expressed mainly in the hematopoietic system) for the treatment of B-cell malignancies. Based on his previous description of the contribution of PI3Kδ in the differentiation of regulatory T cells, which inhibit the effector cytotoxic T cells, he proposes that PI3Kδ inhibition in cancer might render effector T cells more active against the tumor. PI3Kδ inhibitors could therefore be useful in immunotherapy by reducing regulatory T cells. However, when tested, they found that PI3Kδ inhibitors did not cooperate with therapies directed to block CTLA4 or PD1. By contrast, PI3Kδ inhibitors synergized with inhibitors for CSF1R (Lim et al., 2018). A possible explanation for this cooperation could be that CSF1 activates macrophages, which in turn facilitate metastasis of surrounding tumor cells.

This session discussed several aspects that might improve the efficacy of PI3K inhibitors for cancer treatment. In addition to scoring PI3K/PTEN mutations, we should consider that the expression of PI3K regulators, such as p85β, might also make a tumor dependent on PI3K activity. A change in protocols for compound administration (lowering the doses) and the use of selective PI3K inhibitors, as well as inhibitors of the hematopoietic isoforms (PI3Kγ and PI3Kδ) for immunotherapy, should also be borne in mind for the future.

Taken together, the data discussed here have enriched our understanding of the mechanisms of tumorigenesis induced by PI3K, its actions on the organism, and the resistance mechanisms generated upon treatment with PI3K inhibitors. This should help to delineate new strategies for cancer treatments aimed at blocking the action of PI3K.


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