Chapter 5: Lipid Structure and Function

A fatty acid is a long hydrocarbon chain with a carboxylic acid group at one end. Most natural fatty acids have an even number of carbons (typically 14-24) because they are built two carbons at a time during fatty acid synthesis.

Saturated vs. Unsaturated

• Saturated fatty acid: no carbon-carbon double bonds. The chain is a straight rod. Packs tightly → solid at room temperature (butter, lard, tropical oils).
• Unsaturated fatty acid: one or more C=C double bonds. Each cis double bond puts a kink in the chain. Kinked chains cannot pack tightly → liquid at room temperature (olive oil, canola oil, fish oil).

Cis vs. Trans

Naturally occurring unsaturated fatty acids are almost always cis, which puts a sharp bend in the chain.

Trans fats are mostly industrial - produced by partial hydrogenation of vegetable oils. The trans double bond does NOT kink the chain, so trans fats behave more like saturated fats (solid, pack tightly). This is why trans fats raise LDL and lower HDL, contributing to cardiovascular disease. Most developed countries now restrict artificial trans fats.

Omega Numbering and Essential Fatty Acids

Fatty acids can be numbered two ways:

• Delta numbering starts from the carboxyl (C1). A delta-9 double bond is between C9 and C10.
• Omega numbering starts from the methyl end. Omega-3 means the first double bond is 3 carbons from the omega (methyl) end.

Humans cannot introduce double bonds past C9 from the carboxyl end, so we cannot synthesize omega-3 or omega-6 fatty acids. These are essential fatty acids and must come from the diet. Omega-3s (like alpha-linolenic acid, EPA, DHA) are found in fish and flaxseed. Omega-6s (like linoleic acid) are in most vegetable oils.

A triacylglycerol (triglyceride, TAG) is glycerol with three fatty acids attached by ester bonds. This is the body’s main form of stored energy.

Why Fat is Energy-Dense

• Fat yields about 9 kcal per gram.
• Carbohydrate and protein yield about 4 kcal per gram.

Fat stores more than twice the energy per gram because its carbons are more reduced. Fatty acid chains are long stretches of C-H bonds with few oxygens. Each C-H bond is a high-energy electron waiting to enter the electron transport chain. Carbohydrates are already partially oxidized (lots of C-O bonds), so they have fewer electrons per gram to donate.

Fat is also stored without water. Glycogen is stored bound to water (about 2 g water per gram glycogen). A gram of fat stores pure energy with no extra water weight.

Storage and Release

Triglycerides are stored in adipocytes (fat cells) as a single large droplet. Mobilization happens in response to low-energy signals:

• Glucagon and epinephrine activate hormone-sensitive lipase (HSL) in adipose via cAMP and PKA. HSL hydrolyzes triglycerides into glycerol and free fatty acids, which are released into blood.
• Insulin opposes this. In the fed state, insulin inhibits HSL and activates lipoprotein lipase at capillaries, promoting fat storage.

The liberated fatty acids travel bound to albumin to tissues that need fuel. Glycerol goes to the liver, where it enters glycolysis as dihydroxyacetone phosphate (via glycerol kinase).

Saponification is the base-catalyzed hydrolysis of a triglyceride (or any ester) into its alcohol and the salt of its carboxylic acid. For a triacylglycerol, the products are glycerol and three fatty acid salts. The fatty acid salts are soap.

The Reaction

$\text{Triglyceride} + 3\,\text{NaOH} \rightarrow \text{Glycerol} + 3\,\text{fatty acid salts (Na}^+\text{)}$

Strong base (usually NaOH for hard soaps, KOH for soft soaps) attacks each ester carbonyl, cleaving the ester and leaving the carboxylate anion. Sodium (or potassium) counterions form the salt.

Why Soap Cleans

A soap molecule is amphipathic. One end is ionic (the carboxylate COO-), which loves water. The other end is a long hydrocarbon tail, which loves grease. When soap is added to water containing oil, the molecules arrange into micelles - little spheres with hydrophobic tails pointing inward (trapping oil) and hydrophilic heads facing out (in water). The oil is now suspended in water and can be rinsed away.

Saponification vs. Hydrolysis

Ester hydrolysis can happen in acidic or basic conditions. In the body, lipases (hydrolases) break ester bonds without base - they use water and acid/base catalysis within the active site. The pure-chemistry saponification reaction uses excess strong base. Both give the same products.

Phospholipids are the main structural lipids of cell membranes. A phospholipid looks like a triglyceride with one modification: instead of a third fatty acid, it has a phosphate group with a polar head group.

Structure

A phospholipid has:

• A glycerol backbone.
• Two fatty acid tails on C1 and C2 (one saturated, one unsaturated is common).
• A phosphate on C3, linked to a polar head group (choline, ethanolamine, serine, inositol, or glycerol).

The phosphate head is hydrophilic (charged). The two fatty acid tails are hydrophobic. That makes phospholipids amphipathic - one end loves water, the other hates it.

The Bilayer

In water, amphipathic molecules assemble to hide their hydrophobic parts from water. For phospholipids, the lowest-energy arrangement is a bilayer: two layers with tails facing inward (touching each other, away from water) and heads facing outward (in contact with water on both sides).

Common Head Groups

Different head groups give phospholipids slightly different properties and locations:

Bilayer Fluidity

Membrane fluidity depends on:

• Fatty acid saturation: more unsaturation (kinks) → more fluid. Saturated tails pack tightly → less fluid.
• Chain length: longer tails interact more → less fluid.
• Cholesterol: at high temperature it reduces fluidity (holds things in place). At low temperature it prevents the bilayer from becoming too rigid (keeps things moving). It is a bidirectional stabilizer.
• Temperature: higher temperature → more kinetic motion → more fluid.

Sphingolipids are the second major class of membrane lipids (after glycerophospholipids). They are built on a sphingosine backbone rather than glycerol. They are especially abundant in nervous tissue - myelin is up to 30 percent sphingolipid.

The Building Blocks

• Sphingosine: an 18-carbon amino alcohol with a trans double bond. Not a glycerol.
• Ceramide: sphingosine plus a fatty acid attached via an amide bond to the C2 amine. Ceramide is the parent compound for all sphingolipids.
• Sphingomyelin: ceramide + phosphocholine head group. A phospholipid of the sphingosine family.
• Cerebrosides: ceramide + one sugar (glucose or galactose).
• Gangliosides: ceramide + complex sugar chain containing sialic acid.

Sphingolipids in Myelin and Signaling

Myelin wraps axons to speed electrical conduction. It is built of concentrated lipid layers with a high sphingolipid content, including sphingomyelin and glycosphingolipids. Damage to myelin (demyelination) slows nerve conduction - the clinical hallmark of multiple sclerosis.

Sphingolipids are also bioactive signaling molecules. Ceramide, sphingosine, and sphingosine-1-phosphate (S1P) regulate apoptosis, cell proliferation, and immune cell trafficking. S1P is the target of an approved multiple sclerosis drug class (S1P receptor modulators).

Lysosomal Storage Diseases

Sphingolipids are degraded in lysosomes by a chain of enzymes. A defect in any single enzyme causes the specific sphingolipid upstream to accumulate and damage the cell. These sphingolipidoses are classic genetic lysosomal storage diseases.

Cholesterol is the starting material for every steroid hormone, bile acids, and vitamin D. It is also a major component of cell membranes. All steroids share the same four-ring nucleus.

The Four-Ring Skeleton

• Three six-membered rings (A, B, C).
• One five-membered ring (D).
• Various modifications (side chains, double bonds, -OH groups) on this core give each specific steroid.

Cholesterol

Cholesterol inserts into the phospholipid bilayer with its -OH near the phosphate heads and its ring system parallel to the fatty acid tails. It acts as a bidirectional stabilizer of membrane fluidity:

• At high temperature, cholesterol reduces fluidity by restricting motion of nearby fatty acid tails.
• At low temperature, cholesterol prevents the bilayer from becoming too rigid by disrupting tight packing.

Most cells can make cholesterol themselves; the liver makes most of the body’s supply. HMG-CoA reductase is the rate-limiting enzyme of cholesterol synthesis. Statins inhibit HMG-CoA reductase.

The Major Steroid Hormones

All steroid hormones are synthesized from cholesterol in the adrenal cortex, gonads, or placenta. The five MCAT-relevant classes:

Bile Acids

Cholesterol is oxidized in the liver to bile acids (cholic acid, chenodeoxycholic acid). Bile acids are amphipathic - they emulsify dietary fats in the small intestine, increasing the surface area accessible to pancreatic lipase. Without bile acids, fat absorption is poor (which is why patients with bile duct obstruction develop fatty stools, steatorrhea).

Vitamin D

Vitamin D is a “steroid hormone” technically, despite being called a vitamin. UV light on skin converts 7-dehydrocholesterol to cholecalciferol (vitamin D3). Two hydroxylations (one in liver, one in kidney) make active 1,25-dihydroxyvitamin D, which regulates calcium absorption and bone mineralization.

Terpenes are a huge family of natural products built from repeating 5-carbon units called isoprene (2-methyl-1,3-butadiene). The number of isoprene units classifies the terpene.

The Isoprene Rule

Every terpene is assembled from isoprene units, head-to-tail. The number of units gives the class name:

Terpene vs. Terpenoid

• Terpene: pure hydrocarbon made of isoprene units.
• Terpenoid: a terpene with added oxygens or rearrangements (which is most of them in real biology).

These terms are often used interchangeably, but technically “terpenoid” is broader.

MCAT-Relevant Examples

• Squalene (C30) is the direct precursor of cholesterol. Cyclization of squalene builds the four-ring steroid skeleton.
• Beta-carotene (C40) is a tetraterpene found in carrots, spinach, and other orange/green vegetables. It is cleaved into two molecules of vitamin A (retinol, C20) in your intestines.
• Vitamin A (retinol) (C20) is a diterpene alcohol. Its aldehyde form (retinal) is the visual pigment in rhodopsin; light-induced cis-to-trans isomerization of retinal is the first step of vision.
• Coenzyme Q (ubiquinone) has a long polyprenyl side chain (isoprenoid), giving it lipid solubility to shuttle electrons through the inner mitochondrial membrane.

Waxes are simple esters: one long-chain fatty acid + one long-chain alcohol. Both partners are long hydrocarbon chains, so waxes are hydrophobic, inert, and stable.

Structure

$\text{Fatty acid } (\text{RCOOH}) + \text{Long-chain alcohol } (\text{R'OH}) \rightarrow \text{Wax ester } (\text{RCOOR'})$

The fatty acid is usually 14-36 carbons. The alcohol is usually 16-36 carbons. Two very long tails = solid at room temperature and extremely water-repellent.

Examples

• Beeswax (triacontanyl palmitate and related esters) - comb of bees.
• Lanolin - on sheep wool, used in skin creams.
• Carnauba wax - from palm leaves, used to polish cars and surfboards.
• Plant cuticle - a waxy layer on leaves and fruit that prevents water loss.
• Ear wax (cerumen) - a mixture of wax esters, sebum, and dead cells that traps debris in the ear canal.

Function

Waxes are waterproofing and protective. The hydrocarbon chains form a tight, hydrophobic coating that water cannot penetrate.

Fats are hydrophobic; blood is water. Shipping fat through blood requires a carrier particle: a lipoprotein. Each lipoprotein is a tiny ball with a hydrophobic core of triglycerides and cholesteryl esters, surrounded by a shell of phospholipids, free cholesterol, and proteins called apolipoproteins.

The five main classes differ by density, size, and cargo.

The Five Classes

What Each Class Does

Chylomicrons

Made in the intestine from dietary fat. They carry triglycerides through lymph and blood to tissues. Lipoprotein lipase on capillary endothelium cleaves triglycerides in chylomicrons, releasing free fatty acids to adipose and muscle. The remaining “chylomicron remnant” is cleared by the liver.

VLDL

Made in the liver from endogenous triglycerides (assembled from fatty acids and carbohydrates). VLDL carries fat to tissues similarly to chylomicrons, via lipoprotein lipase. As triglycerides are removed, VLDL shrinks and gets denser, becoming IDL, then LDL.

LDL

LDL is the cholesterol-delivery particle. Cells take up LDL via the LDL receptor (a classic example of receptor-mediated endocytosis). Dysfunctional LDL receptors (as in familial hypercholesterolemia) cause high blood LDL and early cardiovascular disease. Oxidized LDL is a major player in atherosclerotic plaque formation - it is taken up by macrophages that become foam cells in the artery wall.

HDL

HDL scavenges cholesterol from peripheral tissues (including atherosclerotic plaques) and returns it to the liver for disposal or reuse - reverse cholesterol transport. HDL is “good” because the more HDL, the more cholesterol can be cleared from tissues.

Apolipoproteins

The proteins on the surface identify the particle to receptors. A few you should recognize:

• apoB-48: on chylomicrons. Made by intestine.
• apoB-100: on VLDL/IDL/LDL. Made by liver. Binds the LDL receptor.
• apoA-I: on HDL. Activates LCAT, the enzyme that esterifies free cholesterol for transport.
• apoC-II: activates lipoprotein lipase (on chylomicrons and VLDL).
• apoE: mediates clearance of chylomicron remnants and IDL by the liver.

Eicosanoids are lipid signaling molecules made from arachidonic acid, a 20-carbon omega-6 polyunsaturated fatty acid. They do not travel far - they act locally on nearby cells and are rapidly degraded. Three main classes: prostaglandins, thromboxanes, and leukotrienes.

The Arachidonic Acid Branch Point

Phospholipase A2 cleaves arachidonic acid from membrane phospholipids in response to cell damage or hormonal stimulation. Arachidonic acid then goes down one of two pathways:

• COX pathway (cyclooxygenase): produces prostaglandins and thromboxanes.
• LOX pathway (lipoxygenase): produces leukotrienes.

What Each Eicosanoid Does

Prostacyclin and thromboxane are opposites - this balance determines whether a blood vessel clots or stays open.

Why NSAIDs Matter

NSAIDs (nonsteroidal anti-inflammatory drugs) block COX. No COX activity means no prostaglandin/thromboxane production, so:

• Less PGE2 → less pain, less fever, less inflammation (therapeutic).
• Less TXA2 → less platelet aggregation (why low-dose aspirin is used to prevent heart attack and stroke).
• Less gastric PGE2 → less mucus protecting the stomach → NSAIDs can cause ulcers.

Examples: ibuprofen, naproxen, aspirin. Aspirin irreversibly acetylates COX; most others are reversible inhibitors.

Corticosteroids (like prednisone) inhibit phospholipase A2 indirectly (via lipocortin/annexin-1), so they block BOTH the COX and LOX pathways. That is why corticosteroids have broader anti-inflammatory effects than NSAIDs, but also more side effects.

Four vitamins are fat-soluble: A, D, E, K. They are stored in body fat and the liver. Because they are not excreted readily, excess intake can be toxic (unlike water-soluble vitamins, where excess is urinated out). Absorption requires bile acids, so fat malabsorption (e.g., from pancreatic or biliary disease) can lead to deficiency.

Vitamin A (Retinol)

• Role: vision (retinal is the chromophore in rhodopsin), growth, immune function, epithelial maintenance.
• Deficiency: night blindness (the first sign), xerophthalmia (dry, damaged cornea), impaired immunity.
• Sources: liver, eggs, dairy, carotenoids from orange/green vegetables (beta-carotene is cleaved into retinol).

Vitamin D (Cholecalciferol)

• Role: calcium and phosphate homeostasis, bone mineralization. Technically a steroid hormone.
• Deficiency: rickets in children (bowing of growing bones), osteomalacia in adults.
• Sources: sunlight converts 7-dehydrocholesterol to cholecalciferol in skin; also in fatty fish, egg yolks, fortified milk.

Biochemically, vitamin D is activated by two hydroxylations: first in the liver (25-hydroxylation) and then in the kidney (1-alpha-hydroxylation) to produce the active 1,25-dihydroxyvitamin D. This active form binds nuclear receptors and upregulates genes for calcium absorption in the gut.

Vitamin E (Tocopherol)

• Role: membrane antioxidant. Quenches lipid peroxyl radicals in membranes, protecting unsaturated fatty acids from oxidative damage.
• Deficiency: hemolytic anemia (red cell membranes oxidize and lyse), neuromuscular symptoms (rare in developed countries).
• Sources: vegetable oils, nuts, seeds.

Vitamin K (Phylloquinone)

• Role: cofactor for gamma-carboxylation of clotting factors II, VII, IX, X, and proteins C and S. Without vitamin K, these factors cannot bind calcium and clot formation fails.
• Deficiency: bleeding, bruising. Newborns are routinely given vitamin K at birth because they have limited stores and no gut bacteria yet.
• Sources: leafy green vegetables, made by gut flora.

Warfarin, an anticoagulant, blocks vitamin K recycling (vitamin K epoxide reductase), leading to non-functional clotting factors and reduced coagulation.