CH.6 Lipids

Introduction to Lipids

Lipids are oily or fatty substances that play three primary physiological roles:

1) in adipose cells, triglycerides (fats) store energy

2) In cellular membranes, phospholipids constitute a barrier between intracellular and extracellular environments

3) Cholesterol is a special lipid that serves as the building block for the hydrophobic steroid hormones.

cardinal characteristics of a lipid

-Hydrophobicity. Hydrophobic means “water-fearing”. It is important to understand the significance of this. Carbon-carbon and carbon-hydrogen bonds are nonpolar. Hence, substances that contain carbon-carbon and carbon-hydrogen bonds will not dissolve well in water.

Some examples: Table sugar dissolves well in water, but cooking oil floats in a layer above water or forms many tiny oil droplets when mixed with water.

Since water is very polar, polar substances dissolve well in water, these are known as “water-loving” or hydrophilic substances.

-a synonym for hydrophobic is lipophilic and a synonym for hydrophilic is lipophobic.

Fatty Acid Structure

Fatty acids are composed of long, unsubstituted alkanes that end in a carboxylic acid

The chain is typically 14 to 18 carbons long, and because they are synthesized two carbons at a time from acetate, predominantly even-numbered fatty acids are made in human cells.

A fatty acid with no carbon-carbon double bonds is said to be saturated with hydrogen because every carbon atom in the chain is covalently bound to the maximum number of hydrogens.

Unsaturated fatty acids have one or double bonds in the tail. These double bonds are always (Z) (or cis).

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Question: How does the shape of an unsaturated fatty acid differ from that of a saturated fatty acid?

Answer: unsaturated fatty acids is bent, or “kinked” at the cis double bond

Question: If fatty acids are mixed into water, how are they likely to associate with each other?

Answer: The long hydrophobic chains will interact with each other to minimize contacts with water, exposing the changed carboxyl group to the aqueous environment.

Figure 1 (please attach to flashcard) illustrates how free fatty acids interact with an aqueous solution by forming a micelle.

hydrophobic interaction: the force that drives tails into the center of the micelle.

Micelle, hydrophobic interaction and the solvation shell

1. Water forms a solvation shell around each hydrophobic substance. The reason is that H2O has a dipole that likes to be able to share its charges with other polar molecules. A solvation shell allows for the most water-water interaction and the least water-lipid interaction. In the case of fatty-acid micelle, water forms a shell around the spherical micelle with the result being that water interacts with polar carboxylic acid head groups while hydrophobic lipid tails hide inside the sphere.

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Question: how does soap help to remove grease from your hands?

answer: grease is hydrophobic. It does not wash off easily in water because it’s not soluble in water. Scrubbing your hands with soap causes micelles to form around the grease particles.

Triacylglycerols (TG)

The storage form of the fatty acid is fat. The technical name for fat is tryacylglycerol or triglyceride (see Figure 2). The triglyceride is composed of three fatty acids esterified to a glycerol molecule. Glycerol is a three-carbon triol with the formula HOCH2-CHOH-CH2OH. As you can see, it has three hydroxyl groups that can be esterified to fatty acids. IT is necessary to store fatty acids in the relativity inert form of fat because free fatty acids are reactive chemicals.

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The triacylglycerol undergoes reactions of esters, such as base-catalyzed hydrolysis. Soaps are the sodium salts of fatty acids (RCOO-Na+). They are amphipathic, which means they have both hydrophilic and hydrophobic regions. Soap is economically produced by base-catalyzed hydrolysis of triglycerides form animal fat into fatty acid salts (soaps). This reaction is called saponification and is illustrated below.

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Lipases are enzymes that hydrolyze fats. Triacylglycerols are stored in fats cells as an energy source. Fats are more efficient energy storage molecules than carbohydrates for two reasons: packing and energy content

1) Packing: Their hydrophobicity allows fats to pack together much more closely than carbohydrates. Carbohydrates carry a great amount of water-of-solvation (water molecules hydrogen bonded to their hydroxyl groups). In other words, the amount of carbon per unit area or unit weight is much greater in fat droplet than in dissolved sugar. If we could store sugars in a dry, powdery form in our bodies, this problem would be obviated.

2) Energy content: All packing considerations aside, fat molecules store much more energy than carbohydrates. In other words, regardless of what you dissolve it in, a fat has more energy carbon-for-carbon than a carbohydrate. The reason is fats are much more reduced. Remember than energy metabolism begins with oxidation of foodstuffs to release energy. Since carbohydrates are more oxidized to start with, oxidizing them releases less energy. Animals use fat to store most of their energy, storing only a small amount as carbohydrates (glycogen). Plans such as potatoes commonly store a large percentage of their energy as carbohydrates (starch).

Phospholipids and lipid bilayer membranes

Membrane lipids are phospholipids (also called phosphatides) derived from diacylglycerol phosphate or DG-P. Often the phosphate group has even bigger polar molecules attached to it, such as choline (phosphatidylcholine), ethanolamine (phosphatidylethanolamine), and inositol (phosphatidylinositol).

For example, phophatidyl choline is phospholipid formed by the esterification of a choline molecule [HO(CH₂)₂N+(CH₃)₃] to the phosphate group of DG-P. Phosphatidylcholine and phosphatidylethanolamine are the most common phospholipids in eukaryotic cells. Beyond its role as a membrane lipid, phosphatidylcholine is am major lipid component of lung surfactant (important in reducing surface tension inside lung alveoli), and phosphatidylinositol plays a role in signal transmission across cell membranes.

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We saw above how fatty acids spontaneously form micelles. Phospholipids also minimie their interactions with water by forming an orderly structure-in this case, it is a lipid bilayer (insert Figure 5 to the flashcard). Hydrophobic interactions drive the formation of the bilayer, and once formed, it is stabilized by van der Waals forces between the long tails.

A more precise way to give the answer to the question above is to say that double bonds (unsaturation) in phospholipid fatty acids tend to increase membrane fluidity. Unsaturation prevents the membrane from solidifying by disrupting the orderly packing of the hydrophobic lipid tails. The right amount of fluidity is essential for function. Decreasing the length of fatty acid tails also increases fluidity. The steroid cholesterol (discussed a bit later) is a third important modulator of membrane fluidity. At low temperatures, it increases fluidity in the same way as kinks in fatty acid tails; hence, it is known as membrane antifreeze. At high temperatures, however, cholesterol attenuates (reduces) membrane fluidity. Don’t ponder this paradox too long; just remember that cholesterol keeps fluidity at optimum level. Remember, the structural determinants of membrane fluidity are: degree of saturation, tail length, and amount of cholesterol.

The lipid bilayer acts like a barrier surrounding the cell in the sense that it separates the interior of the cell from the exterior. However, the cell membrane is much more complex than a simple barrier; it is dynamic structure that regulates what comes into and goes out of the cell and transmits extracellular signals to the interior of the cell. Proteins embedded into the plasma membrane play a big role in this. Since the plasma bilayer membrane surrounding the cells is impermeable to charged particles such as Na+, protein gate-ways such as in channels are required for ions to enter or exit cells. Further, certain hormones (peptides) cannot pass through the cell membrane due to their charged nature; instead protein receptors in the cell membrane bind these hormones and transmit a signal into the cell in a second messenger cascade.

Would a saturated or unsaturated fatty acid residue have more van der Waals interactions with neighboring alkyl chains in a bilayer membrane?

Terpenes and steroids

A terpene is a membrane of a broad class of compounds built from isoprene units (C3H8) with a general formula (C5H8)_n.

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Terpenes may be linear or cyclic, and they are classified by the number of isoprene units they contain. For example, monoterpenes consist of two isoprene units, sesquiterpenes consist of three, and diterpenes consist of four.

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Squalene is a triterpene (made of six isoprene units), and is it a particularly important compound, as it is biosynthetically utilized in the manufacture of steroids. Squalene is also a component of earwax.

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Whereas terpene is formally a simply hydrocarbon, there are a number of natural and synthetically derived species that are built from an isoprene skeleton and functionalized with other elements (O,N,S,etc.). These functionalized terpenes are known as terpenoids. Vitamin A (C₂₀H₃₀O) is an example of a terpenoid.

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Steroids

Steroids are included here because of their hydrophobicity, and hence, similarity to fats. Their structure is otherwise unique. All steroids have the basic tetracyclic ring system (insert Figure 10 to this flashcard), based on the structure of cholesterol, a polycyclic amphipath. (Polycyclic means several rings, and amphipathic means diplaying both hydrophilic and hydrophobic characteristics).

Ad discussed earlier, the steroid cholesterol is an important component of the lipid bilyaer. It is both obtained from the diet and synthesized in the liver. It is carried in the blood packaged with fats and proteins int lipoproteins. One type of lipoprotein has been implicated as the cause of atherosclerotic vascular disease. Which refers to the build-up of cholesterol “plaques” on the inside of blood vessels.

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Steroid hormones are made from cholesterol. Two examples are testosterone (an androgen or male sex hormone) and estradiol (an estrogen or female sex hormone). There are no receptors for steroid hormones on the surface of cells’ because steroids are highly hydrophobic, they can diffuse right through the lipid bilayer mmebrane into the cytoplasm. The receptors for steroid hormoones are located within cells rather than on the cell surface. This is an important point! You must be aware of the contrast between peptide hormones, such as insulin, which exert their effects by binding to receptors at the cell-surface, an steroid hormones, such as estrogen, which diffuse into cells to find their receptors.

Other lipids

Beyond Fatty acids, triglycerides, phospholipids, terpenes, and cholesterol, and steroids, there are a few others lipids with which you should be familiar for the MCAT.

-sphingolipids

-waxes

-fat soluble vitamins

-prostaglandins

Sphingolipids

Sphingolipids are structured in a similar manner as phospholipids, except that the backbone is sphingosine instead of glycerol.

The only significant sphingolipid in humans is sphingomyelin, an important component of the myelin sheath around neurons.

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Waxes

Waxes are long chain fats esterified to long chain alcohols. They are extremely hydrophobic and often form waterproof barriers, most notably in plans. Animals also use waxes to form a protective barrier (ex: earwax).

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Fat-soluble Vitamins

Fat-soluble vitamins are absorbed with dietary fat and stored in adipose tissue and in the liver. The four fat soluble vitamins are vitamins A, D, E, and K; all of them having ring structures. Vitamin A is a terpenoid essential for vision, growth, epithelial maintenance, and immune function. Vitamin D is derived from cholesterol (it is a steroid) important in regulating blood levels in calcium and phosphate. Vitamin E is actually a group of compounds, called tocopherols (methylated phenols), that are important as antioxidants. Alpha-tocopherol is the most active Vitamin E. Vitamin K serves as an important coenzyme in the activation of clotting proteins.

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Prostaglandins

Prostaglandins belong to a group of molecule known as eicosanoids, derived from 20-carbon fatty acids (the prefix eicosa means “20”). They have vastly different roles in different tissues, depending on the receptor to which they bind. Their roles including regulating smooth muscle contraction in the intestines and uterus, regulating blood vessel diameter, maintaining gastric integrity (by decreasing acid secretion and increasing mucous secretion, among others. They have all the same general structure, including a five-membered ring.

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Fatty Acid Oxidation

Following the initial steps in fat digestion, chylomicrons composed of fat and lipoproteins are transported via the lymphatic system and blood stream to the liver, heart, lungs, and other organs. This dietary fat, or triacylglercol, is then hydrolyzed to liberate free fatty acids which can then under B-oxidation. This process begins at the outer mitochondrial membrane with the activation of the fatty acid. This reaction, catalyzed by acyl-CoA synthetase, requires the investment of two ATP equivalents to generate fatty acyl-CoA which is then transported into the mitochondrion.

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Once in the matrix, the fatty acyl-CoA undergoes a repeated series of four reactions which cleave the bond between the alpha and beta carbons to liberate an acetyl-CoA in addition to generating one FADH2 and NADH.

Each round of Beta Oxidation cleaves a two-carbon acetyl-CoA from the molecule; however, the final around cleaves a four-carbon fatty acetyl-CoA to generate two acetyl-CoA. For instance, the complete B-oxidation of lauric acid (a twelve-carbon saturated fatty acid) involves the following: an investment of two ATP equivalents to convert it to a fatty acyl-CoA and then five rounds of B-oxidation. This generates five FADH2, five NADH, and six acetyl-CoA which can then enter the Krebs Cycle. When these six acetyl-CoA go through the Krebs Cycle, they will generate an additional 18 NADH, 6 FADH2, and 6 GTP.

We then have a grand total of 11 FADH2 (five from B-oxidation, and six from Krebs Cycle), 23 NADH (five from B-oxidation, and 18 from the Krebs Cycle), and six ATP equivalents (from the Krebs Cycle). After the electron transport chain (and subtracting the two ATP equivalents required at the beginning of B-oxidation), we obtain 78 ATP from lauric acid.

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Ketogenesis

During periods of starvation, glycogen stores become exhausted and blood glucose falls significantly. To help supply the central nervous system with energy when glucose is in short supply, the liver generates ketone bodies via a process in the mitochondrial matrix known as ketogenesis. The ketone bodies are generated from acetyl-CoA and include acetone, acetoacetate, and B-hydroxylbutyrate. These molecules can cross the blood-brain barrier and be converted back to acetyl-CoA once they arrive at their target organ; the acetyl-CoA can then enter the Krebs Cycle.

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In some circumstances, ketogenesis can take place when adequate glucose is present in the blood but cannot enter the cell. This can occur, for example, when a patient is suffering from type I diabetes does not receive an insulin injection for a prolonged period of time. Without insulin, glucose cannot enter cells in order to be used for energy, and the patient levels of acetyl-CoA are so high , many of them get converted into ketone bodies. Ketone bodies are acidic, and this can result in diabetic ketoacidosis. which is a potentially life-threating condition. Patients commonly experience fatigue, confusion, and fruity-scented breathe due to the acetone (which is very volatile) present in their blood. This combination of symptoms has even led to patients being mistakenly classified as intoxicated and arrested for driving under the influence.

Fatty acid synthesis

The de novo synthesis of fatty acids is reminiscent of B-oxidation with several notable exceptions. While the fatty acid catabolism occurs in the mitochondrial matrix, anabolism takes place with the cytoplasm. This compartmentalization allows for easier regulation, since the enzymes required for synthesis and break down are separated. Much of B-oxidation involved the removal of two-carbon subunits. Rather than building the nascent fatty acid directly with acetyl-CoA, acetyl-CoA is first activated in a carboxylation reaction. The activation is the committed step in fatty acid synthesis and requires the investment of ATP; it is faciliated by acetyl-CoA carboxylase to generate malonyl-CoA.

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Fatty acid synthase is a large enzyme with multiple catalytic domains. Acetyl-CoA first binds to a domain known as the acyl carrier protein (ACP). It is then shifted to another domain on the enzyme with a cysteine residue, and malonyl-CoA binds to the ACP. The acetyl group condenses with the malonyl group as the malonyl is decarboxylated. (Recall that the successive addition, then removal of CO2 can drive unfavorable conditions; this same process occurs in gluconeogenesis with the carboxylation of pyruvate to oxaloacetate, and the subsequent decarboxylation of oxaloacetate to PEP.) The ACP domain now holds a four-carbon unit, which undergoes two reductions. This process requires the reducing power of NADPH, which is generally obtained from the pentose phosphate pathway (see chapter 5).

The saturated four carbon acyl unit is shifted to the domain with the cysteine residue, and another malonyl-CoA binds to the ACP. The process then repeats: the four-carbon unit condenses with malonyl as CO2 is lost, two successive reductions occur, and now the six-carbon chain is shifted to the cysteine residue.

Once a sixteen-carbon long fatty acid is generated, additional enzymes aid in further modification of the fatty acid (ex: addition of functional groups and elongation). Note that this process requires no template (nor does glycogen or amino acid synthesis), which means that nothing is “read” to generate the products. The differs from the template-based syntheses of polypeptides (mRNA is “read” to generate an amino acid sequence) and nucleic acids (DNA is “read” to generate DNA during replication and RNA during transcription).

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Amino Acid Catabolism and Metabolic Summary

We discussed amino acid structure and protein structure and function in Chapter 4, but we haven’t yet touched on the idea of proteins as fuel. Proteins in the cell are constantly being made, kept for a certain period of time (minutes to weeks), and then degraded back into amino acids. In addition, humans absorb amino acids from dietary proteins. These free amino acids can be catabolized via several pathways. They can be taken up by cells and be used to make cellular proteins. The amino group can be removed and either used to synthesize nitrogenous compounds, such as nucleotide bases, or it can be converted into urea for excretion. The remaining carbon skeleton (called alpha-keto acid) can either be broken down into water and CO2, or it can be converted to glucose (glucogenic amino acids) or acetyl-CoA (ketogenic amino acids)

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Metabolism Summary

Generally speaking, cells prefer to use carbohydrates as fuel. When blood sugar is high, cells will take up glucose and make ATP via glycolysis. Liver and muscle cells will also store glucose as glycogen (glycogenesis) and the lvier can also take some of the acetyl-CoA generated by the pyruvate dehydrogenase complex to make fatty acids (fatty acid synthesis). These are converted into tryglycerides and stored in adipose tissue. These pathways are shown in black in Figure 21

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When blood sugar levels fall (starved state), the liver will break down stored glycogen (glycogenolysis) and release glucose into the bloodstream. It will also begin the process of gluconeogenesis to synthesize “new” glucose that can also be released into the bloodstream. This glucose can be taken up by other body cells and use in glycolysis to generate ATP. These pathways are shown in green in figure 21.

If the starved state continues past the point where all glycogen stores are used (12-24 hours), then fatty acid breakdown will occur. Triglycerides from adipose tissue are broken down into free fatty acids and glycerol that are released into the bloodstream. Cells will take up fatty acids and run B-oxidation. The liver can use the glycerol to generate glucose in gluconeogenesis. Some of the acetyl-CoA made in B-oxidation is used to turn the Krebs Cycle, and some is converted into Ketone bodies (Ketogenesis). These pathways are shown in red in Figure 21.

Finally, proteins and amino acids can be used as fuel. The carbon skeleton of the amino acids can be used in gluconeogenesis (glucogenic amino acids) or to make acetyl-CoA and ketone bodies (ketogenic amino acids).