Table of Contents
- Introduction to Lipids
- Energy Context: Catabolism and Energy Sources
- Classification of Lipids
- Fatty Acids
- Glycerides (Neutral Lipids)
- Phospholipids
- Waxes
- Steroids and Cholesterol
- Plasma Lipoproteins
- 9.1 Chylomicrons
- 9.2 VLDL
- 9.3 LDL (Bad Cholesterol)
- 9.4 HDL (Good Cholesterol)
- 9.5 Fat Digestion and Absorption
- Clinical Relevance: Lifestyle and Lipid Levels
- Summary and Conclusion
1. Introduction to Lipids
The term lipid does not refer to a single type of molecule, but rather to a chemically diverse collection of organic molecules that share one defining physical property: solubility in nonpolar (organic) solvents (e.g., chloroform, ether) and insolubility in water.
This shared characteristic arises from the predominance of nonpolar hydrocarbon regions in their structure, making them hydrophobic to varying degrees.
Functions of Lipids in Living Organisms
Lipids serve a remarkably wide range of biological roles:
| Function | Details |
|---|---|
| Energy source | Like carbohydrates, lipids are an excellent source of metabolic energy |
| Energy storage | Most body energy reserves are stored as triglycerides in adipocytes (fat cells) |
| Membrane structural components | Phosphoglycerides, sphingolipids, and cholesterol form the basic structure of all cell membranes |
| Hormones | Steroid hormones are chemical messengers enabling communication between distant tissues |
| Lipid-soluble vitamins | Vitamins A, D, E, and K are lipid-soluble and regulate critical processes including blood clotting and vision |
| Protection | Adipose tissue acts as a cushioning shock absorber for vital organs |
| Thermal insulation | Subcutaneous fat helps maintain body temperature |
Context note: Lipids are central to both structural biology (membranes) and metabolic physiology (energy). Their diverse functions explain why disruptions in lipid metabolism underlie so many diseases, from cardiovascular disease to metabolic syndrome.
2. Energy Context: Catabolism and Energy Sources
To understand why lipids matter, it helps to place them within the broader context of energy metabolism.
How the Body Generates Heat and Energy
Body heat is generated from two processes:
- Nutrient oxidation → produces ATP (via catabolism of glucose, fatty acids, amino acids)
- ATP utilization → energy released from ATP hydrolysis is used for cellular work; some is lost as heat
The central metabolic pathways can be simplified as:
- CATABOLISM (breaking down): Macromolecules (carbohydrates, fats, proteins) → acetyl-CoA → Krebs cycle → electron transport chain → ATP + CO₂ + H₂O. Produces NADH and FADH₂ as electron carriers.
- ANABOLISM (building up): Uses ATP energy to synthesize complex molecules from simpler precursors.
Comparison of Energy Storage: Glycogen vs. Fat
| Feature | Glycogen | Fat (Triglycerides) |
|---|---|---|
| Typical storage duration | ~1 day supply | ~1 month supply (or more) |
| Energy per gram | Lower (~4 kcal/g); ~70% of weight is water | Higher (~9 kcal/g); essentially anhydrous |
| When used | Used first during fasting/exercise | Released after glycogen is depleted |
| Location | Liver, muscle | Adipocytes (adipose tissue) |
Energy Value of Common Nutrients (approximate)
| Nutrient | kcal/gram |
|---|---|
| Carbohydrates | ~4 kcal/g |
| Proteins | ~4 kcal/g |
| Fats | ~9 kcal/g |
| Alcohols | ~7 kcal/g |
Key insight: Fat is the body’s preferred long-term energy storage molecule precisely because it is anhydrous and energy-dense — more than twice the caloric value per gram compared to carbohydrates or protein.
3. Classification of Lipids
Lipids are organized into four main types based on their chemical structure:
LIPIDS
├── Fatty Acids (saturated and unsaturated)
├── Glycerides (glycerol-containing lipids)
│ ├── Monoglycerides
│ ├── Diglycerides
│ └── Triglycerides
├── Nonglyceride Lipids
│ ├── Sphingolipids
│ ├── Steroids (e.g., cholesterol)
│ └── Waxes
└── Complex Lipids
└── Lipoproteins (e.g., LDL, HDL)
A further key distinction is between neutral (nonpolar) lipids and polar lipids:
NEUTRAL LIPIDS POLAR LIPIDS
├── Glycerides ├── Phospholipids
└── Waxes │ ├── Glycerophospholipids
│ └── Sphingolipids
└── Glycolipids
4. Fatty Acids
4.1 Structure and General Properties
A fatty acid is a long-chain monocarboxylic acid, typically with 12–24 carbon atoms in an unbranched chain.
General formula: CH₃-(CH₂)ₙ-COOH
The structure has two distinct chemical regions:
- Hydrophobic (nonpolar) hydrocarbon tail: the long –CH₂– chain; poorly soluble in water
- Hydrophilic (polar) carboxylic head group (–COOH): ionized to –COO⁻ at physiological pH (pH 7.4)
Because they are ionized at physiological pH, fatty acids exist as carboxylate anions in the body. This is why the more biochemically precise terms are:
- palmitate (not palmitic acid)
- stearate (not stearic acid)
- oleate (not oleic acid)
In living organisms, free fatty acids are found only in small quantities; they are usually found as covalent components of larger lipid molecules (e.g., triglycerides, phospholipids).
4.2 Classification of Fatty Acids
Fatty acids are classified based on:
A. Chain Length
| Category | Number of Carbon Atoms |
|---|---|
| Short-chain | 1–5 C |
| Medium-chain | 6–12 C |
| Long-chain | 13–20 C |
| Very long-chain | >20 C |
B. Degree of Saturation (Presence of C=C Double Bonds)
| Type | Double Bonds | Example |
|---|---|---|
| Saturated fatty acids | None (0) | Stearic acid (C18:0) |
| Monounsaturated fatty acids | 1 | Oleic acid (C18:1) |
| Polyunsaturated fatty acids (PUFA) | ≥2 | Linoleic acid (C18:2), Arachidonic acid (C20:4) |
Important biological note: Double bonds in almost all naturally occurring unsaturated fatty acids are in the CIS configuration. The trans configuration is a byproduct of industrial partial hydrogenation (used to produce margarine) and is associated with adverse cardiovascular effects.
C. Position of Double Bonds
The double bonds in polyunsaturated fatty acids are NOT conjugated (i.e., they are not alternating single-double-single-double). Instead, they are separated by one methylene (–CH₂–) group:
–CH=CH–CH₂–CH=CH– (methylene-interrupted pattern)
NOT: –CH=CH–CH=CH– (conjugated pattern)
4.3 Cis-Trans Isomerism
The geometry of the double bond has profound consequences for molecular shape and biological function.
- Cis bond: The two hydrogen atoms on either side of the double bond are on the same side → creates a rigid “kink” or bend in the hydrocarbon chain
- Trans bond: The two hydrogen atoms are on opposite sides → the chain remains nearly straight, similar to a saturated fatty acid
Biological consequence of cis double bonds: The kink introduced by a cis double bond prevents the tight packing of fatty acid chains. This directly lowers the melting point and increases membrane fluidity (see Section 4.5 and 6.3).
Example illustration: Imagine trying to stack bent sticks (cis fatty acids) vs. straight sticks (saturated fatty acids). Straight sticks pack tightly; bent sticks leave gaps — this is what happens in cell membranes.
4.4 Nomenclature Systems
There are three parallel systems used to name fatty acids:
A. Trivial (Common) Names
These are historical names still widely used:
- Palmitic acid, Stearic acid, Oleic acid, Linoleic acid, etc.
B. IUPAC Systematic Names
Based on the parent hydrocarbon chain:
Rules for IUPAC naming:
- Name is based on the number of carbon atoms in the chain
- Saturated fatty acids end with the suffix –anoic (e.g., octadecanoic acid = stearic acid)
- Unsaturated fatty acids end with the suffix –enoic (e.g., octadecenoic acid = oleic acid)
- Carbon atoms are numbered from the carboxyl carbon = C-1
- The position of each double bond is indicated by the number of the lower-numbered carbon in the double bond, preceded by Δ (delta)
Example:
- Oleic acid = cis-Δ9-octadecenoic acid = C18:1 Δ9 → 18 carbons, 1 double bond, located between C9 and C10, cis configuration
IUPAC numerical multipliers (for reference):
| Number | Prefix | Number | Prefix |
|---|---|---|---|
| 1 | mono- | 14 | tetradeca- |
| 2 | di- | 15 | pentadeca- |
| 3 | tri- | 16 | hexadeca- |
| 4 | tetra- | 17 | heptadeca- |
| 5 | penta- | 18 | octadeca- |
| 6 | hexa- | 19 | nonadeca- |
| 7 | hepta- | 20 | icosa-/eicosa- |
| 8 | octa- | 22 | docosa- |
| 9 | nona- | 24 | tetracosa- |
| 10 | deca- |
C. Omega (ω) / n- Notation
This system numbers carbons from the methyl (–CH₃) end, designated as omega (ω) or n.
- The position of the first double bond counting from the methyl end defines the omega class:
- ω-3 (n-3): first double bond at C3 from methyl end → e.g., α-linolenic acid
- ω-6 (n-6): first double bond at C6 from methyl end → e.g., linoleic acid, arachidonic acid
- ω-9 (n-9): first double bond at C9 from methyl end → e.g., oleic acid
Shorthand Notation
Fatty acids are described as: C(number):(double bonds) Δ(position(s))
| Trivial Name | IUPAC Name | Shorthand |
|---|---|---|
| Palmitic acid | Hexadecanoic acid | C16:0 |
| Stearic acid | Octadecanoic acid | C18:0 |
| Oleic acid | cis-9-Octadecenoic acid | C18:1 Δ9 or 18:1 (ω-9) |
| Linoleic acid | cis,cis-9,12-Octadecadienoic acid | C18:2 Δ9,12 or 18:2 (ω-6) |
| α-Linolenic acid (ALA) | cis-9,12,15-Octadecatrienoic acid | C18:3 Δ9,12,15 or 18:3 (ω-3) |
| Arachidonic acid | cis-5,8,11,14-Eicosatetraenoic acid | C20:4 Δ5,8,11,14 or 20:4 (ω-6) |
| EPA | cis-5,8,11,14,17-Eicosapentaenoic acid | C20:5 Δ5,8,11,14,17 or 20:5 (ω-3) |
| DHA | cis-4,7,10,13,16,19-Docosahexaenoic acid | C22:6 Δ4,7,10,13,16,19 or 22:6 (ω-3) |
I have to remember these:
Palmitic (C16:0) → Palmoleic (C16:1, Δ9)
Stearic (C18:0) → Oleic (C18:1, Δ9) → Linoleic (C18:2, Δ9,12) → a-Linolenic (C18:3, Δ9,12,15)
Linoleic [Omega 6] (C18:2, Δ9,12) → Arachidonic (C20:4, Δ5,8,11,14)
a-Linolenic [Omega 3] (C18:3, Δ9,12,15) → Eicosapentanoic (C20:5, Δ5,8,11,14,17)
a-Linolenic [Omega 3] (Δ18:3, Δ9,12,15) → Decosahexanoic (C22:6, Δ4,7,10,13,16,19)
(Il delta fa +3)
Example worked problem – Arachidonic acid:
- Using Δ notation: C20:4 Δ5,8,11,14 → 20 carbons, 4 double bonds at C5, C8, C11, C14 (numbered from carboxyl end)
- Using ω notation: C20:4 ω-6 → counting from the methyl end, the first double bond is at position 6
4.5 Physical Properties
Effect of Chain Length and Saturation on Melting Point
Rule 1: As chain length increases, melting point increases (more surface area = stronger van der Waals interactions between chains).
Rule 2: Unsaturated fatty acids have lower melting points than the corresponding saturated fatty acid with the same number of carbons.
Rule 3: As the number of double bonds increases, the melting point decreases further.
Why? The cis double bond introduces a rigid kink into the chain, disrupting the regular packing of molecules. This makes it easier for the molecules to separate (lower melting point) and explains why oils (polyunsaturated) are liquid at room temperature while saturated fats are solid.
At Room Temperature (25°C):
- Saturated and long-chain fatty acids → generally SOLID (e.g., butter, beef fat)
- Unsaturated or short-chain fatty acids → generally LIQUIDS (e.g., olive oil)
Imagine this:
- (c) Saturated fatty acids in their fully extended form pack in a compact, stabilized arrangement with many van der Waals interactions between the straight hydrocarbon chains.
- (d) A mixture containing unsaturated fatty acids — the cis double bond creates a kink, interfering with this tight packing and producing a less stable, more fluid arrangement.
4.6 Common Fatty Acids
Common Saturated Fatty Acids
| Common Name | IUPAC Name | Carbons | Melting Point (°C) | Formula |
|---|---|---|---|---|
| Capric | Decanoic | C10:0 | 32 | CH₃(CH₂)₈COOH |
| Lauric | Dodecanoic | C12:0 | 44 | CH₃(CH₂)₁₀COOH |
| Myristic | Tetradecanoic | C14:0 | 54 | CH₃(CH₂)₁₂COOH |
| Palmitic | Hexadecanoic | C16:0 | 63 | CH₃(CH₂)₁₄COOH |
| Stearic | Octadecanoic | C18:0 | 70 | CH₃(CH₂)₁₆COOH |
| Arachidic | Eicosanoic | C20:0 | 77 | CH₃(CH₂)₁₈COOH |
| Lignoceric | Tetracosanoic | C24:0 | — | CH₃(CH₂)₂₂COOH |
Common Unsaturated Fatty Acids
| Common Name | IUPAC Name | Carbons | Double Bonds | Position(s) | MP (°C) |
|---|---|---|---|---|---|
| Palmitoleic | cis-9-Hexadecenoic | C16:1 | 1 | Δ9 | 0 |
| Oleic | cis-9-Octadecenoic | C18:1 | 1 | Δ9 | 16 |
| Linoleic (EFA) | cis,cis-9,12-Octadecadienoic | C18:2 | 2 | Δ9,12 | −5 |
| α-Linolenic (EFA) | All-cis-9,12,15-Octadecatrienoic | C18:3 | 3 | Δ9,12,15 | −11 |
| Arachidonic | All-cis-5,8,11,14-Eicosatetraenoic | C20:4 | 4 | Δ5,8,11,14 | −50 |
| EPA | All-cis-5,8,11,14,17-Eicosapentaenoic | C20:5 | 5 | Δ5,8,11,14,17 | — |
| DHA | All-cis-4,7,10,13,16,19-Docosahexaenoic | C22:6 | 6 | Δ4,7,10,13,16,19 | — |
The 18-carbon family — a key set to know:
Stearic acid (18:0):
CH₃-(CH₂)₇-CH₂-CH₂-(CH₂)₇-COOH → no double bonds, solid
Oleic acid (18:1 cis-Δ9, ω-9):
CH₃-(CH₂)₇-CH=CH-(CH₂)₇-COOH → 1 double bond at C9
Linoleic acid (18:2 cis-Δ9,12, ω-6):
CH₃-(CH₂)₄-CH=CH-CH₂-CH=CH-(CH₂)₇-COOH → 2 double bonds (ESSENTIAL)
α-Linolenic acid (18:3 cis-Δ9,12,15, ω-3):
CH₃-CH₂-CH=CH-CH₂-CH=CH-CH₂-CH=CH-(CH₂)₇-COOH → 3 double bonds (ESSENTIAL)
4.7 Essential Fatty Acids and Eicosanoids
Essential fatty acids (EFAs) are those that cannot be synthesized by the human body and must be obtained from the diet. The two parent EFAs are:
- Linoleic acid (LA) — ω-6, C18:2
- α-Linolenic acid (ALA) — ω-3, C18:3
The human body lacks the enzymes needed to introduce double bonds beyond C9 (counting from the carboxyl end), which is why linoleic (Δ9,12) and linolenic (Δ9,12,15) acids cannot be made endogenously.
Metabolic Pathways from EFAs
Once ingested, LA and ALA can be converted to longer-chain, more highly unsaturated derivatives:
Omega-6 pathway:
Linoleic acid (18:2 ω-6)
↓
γ-Linolenic acid / GLA (18:3 ω-6)
↓
Dihomo-γ-linolenic acid / DGLA (20:3 ω-6)
↓
Arachidonic acid / AA (20:4 ω-6) ← key intermediate
↓
Docosapentaenoic acid / DPA (22:5 ω-6)
Omega-3 pathway:
α-Linolenic acid (18:3 ω-3)
↓
Stearidonic acid / SDA (18:4 ω-3)
↓
Eicosatetraenoic acid (20:4 ω-3)
↓
EPA (20:5 ω-3) ← fish oils, anti-inflammatory
↓
DPA (22:5 ω-3)
↓
DHA (22:6 ω-3) ← brain, retina
Note: The conversion of ALA → EPA → DHA is possible but very inefficient in humans. Therefore, it is recommended to obtain EPA and DHA directly from dietary sources (oily fish, algae oil).
Eicosanoids: Hormone-Like Lipid Mediators
Arachidonic acid (AA, C20:4 ω-6) is the precursor for a family of highly potent biological regulators called eicosanoids, which include:
- Prostaglandins
- Leukotrienes
- Thromboxanes
These are not classical hormones (they are not produced in a specialized gland and transported through the bloodstream), but they act as powerful local regulators with far-reaching effects.
Eicosanoid Synthesis Pathway (from Arachidonic Acid):
Arachidonic acid
├─── Lipoxygenase pathway ──→ LEUKOTRIENES
│ (Inflammation, bronchoconstriction,
│ vasoconstriction, capillary permeability)
│
└─── Cyclooxygenase (COX) pathway ──→ PGH₂ (intermediate)
↓ ↓ ↓
PGI₂ PGE₂ / PGF₂α TXA₂
(prostacyclin) (tissue-specific (thromboxane)
Antiplatelet/ prostaglandins) Platelet aggregation
Vasodilation PGE₂: smooth Vasoconstriction
muscle relaxation
PGF₂α: smooth
muscle contraction
Clinical relevance: Aspirin (acetylsalicylic acid) irreversibly inhibits cyclooxygenase (COX), blocking prostaglandin and thromboxane synthesis. This is the basis of its anti-inflammatory and antiplatelet effects (used in cardiovascular prophylaxis).
Omega-3 Eicosanoids
Interestingly, omega-3 fatty acids (EPA and DHA) compete with arachidonic acid for the same enzymes. The eicosanoids derived from omega-3 PUFAs tend to have anti-inflammatory effects, whereas those from omega-6 (arachidonic acid) tend to be pro-inflammatory.
This has led researchers to recommend that omega-6 intake should not exceed 2–4 times the omega-3 intake in the diet.
4.8 Omega-3 and Omega-6 Fatty Acids: Dietary Significance
Best Food Sources
Omega-3 Sources:
- ALA: Flaxseed, chia seeds, walnuts, canola oil, soybean oil
- EPA & DHA: Salmon, albacore tuna, sardines, lake trout, mackerel, krill oil, algae oil
Omega-6 Sources:
- LA: Vegetable oils (sunflower, safflower, corn, soybean), walnuts, Brazil nuts, almonds, pistachios, peanuts
- AA: Meat, poultry, eggs
Dietary Recommendations Summary (ESC/EAS Guidelines):
The European Society of Cardiology guidelines support the following lifestyle interventions for lipid management:
To reduce Total Cholesterol (TC) and LDL-C:
- ↓ Dietary saturated fat (strong evidence)
- ↑ Dietary fiber
- ↓ Dietary cholesterol
- Use of phytosterol-enriched foods
- ↓ Excess body weight
- ↑ Habitual physical activity
- Soy protein products
To reduce Triglycerides (TG):
- ↓ Excess body weight
- ↓ Alcohol intake
- ↓ Mono- and disaccharides
- ↑ Physical activity
- n-3 PUFA supplements
- Replace saturated fat with mono- or polyunsaturated fat
To increase HDL-C:
- ↓ Trans fatty acids (strong evidence)
- ↑ Physical activity
- ↓ Excess body weight
- Moderate alcohol use
- Quit smoking
Priority Pyramid (most to least beneficial):
MOST BENEFICIAL (cardioprotective):
↑ Omega-3 PUFA (EPA, DHA, ALA)
BENEFICIAL:
↑ Omega-6 PUFA (LA, GLA)
↑ Monounsaturated FA (oleic acid, EVOO)
NEUTRAL TO LESS BENEFICIAL:
Saturated FA (myristic, lauric, palmitic, stearic)
[from dairy fat, meat, coconut/palm oil]
MOST HARMFUL:
Trans-Saturated FA (elaidic acid, partially hydrogenated oils)
→ Promotes obesity, dyslipidemia, atherosclerosis
5. Glycerides (Neutral Lipids)
5.1 Triglycerides: Structure
Glycerides are lipid esters formed from glycerol and one, two, or three fatty acids.
Glycerol is a three-carbon alcohol with three hydroxyl (–OH) groups.
Esterification is the reaction between a carboxylic acid (fatty acid) and an alcohol (glycerol –OH), releasing water:
Fatty acid + Glycerol –OH → Ester bond (–COO–) + H₂O
Depending on how many hydroxyl groups are esterified:
- 1 fatty acid → monoglyceride
- 2 fatty acids → diglyceride
- 3 fatty acids → triglyceride (also called triacylglycerol, TAG)
Triglyceride Structure
A triglyceride consists of glycerol esterified at all three positions (sn-1, sn-2, sn-3 — stereospecific numbering) with fatty acids that can be the same or different:
O
‖
H₂C–O–C–R₁ ← sn-1 position (often saturated FA)
O
‖
HC–O–C–R₂ ← sn-2 position (often unsaturated FA)
O
‖
H₂C–O–C–R₃ ← sn-3 position
Physical Properties of Triglycerides
- Completely nonpolar molecules — density lower than water
- All 3 saturated FA: Chains pack tightly together → SOLID at physiological temperature (e.g., 3 palmitic acids)
- Mixed (2 saturated + 1 monounsaturated): The cis double bond of the unsaturated chain prevents tight packing → less dense/more fluid
- All unsaturated: Very poor packing, liquid at room temperature
The four packing patterns (from most to least structured):
- Trisaturated: All three saturated FA → tightest packing, solid
- Disaturated (mono-unsaturated): Two saturated + one unsaturated
- Monosaturated (di-unsaturated): One saturated + two unsaturated
- Triunsaturated: All three unsaturated → loosest packing, most fluid
5.2 Triglycerides: Functions and Storage
Energy Storage
In mammals, most triglycerides are stored in adipose tissue, composed of specialized cells called adipocytes. Within adipocytes, triglycerides accumulate in lipid vacuoles (droplets) within the cytoplasm. Adipose tissue is located:
- Subcutaneously (just beneath the skin) — thermal insulation
- In the abdominal cavity — energy reserve, organ protection
Energy Stores in the Human Body (70 kg lean subject)
| Store | Energy (kcal) |
|---|---|
| Liver triglycerides | ~450 |
| Liver glycogen | ~400 |
| Muscle triglycerides | ~3,000 |
| Muscle glycogen | ~2,500 |
| Adipose tissue triglycerides | ~120,000 |
Clinical note: In subjects with morbid obesity, adipose tissue triglycerides can be approximately 8 times higher than in lean individuals.
Mobilization of Triglycerides
When fatty acids are needed for energy:
- Lipases hydrolyze the ester bonds of triglycerides → free fatty acids + glycerol
- Because of their high hydrophobicity, free fatty acids need carrier proteins (albumin) to travel through the bloodstream to the liver for catabolism.
5.3 Chemical Reactions of Fatty Acids and Glycerides
Esterification
Fatty acids react with alcohols (including glycerol) to form esters and water:
R–COOH + R'–OH → R–COO–R' + H₂O
(fatty acid) (alcohol) (ester) (water)
Hydrogenation (Addition at the Double Bond)
Addition of H₂ across a double bond, converting an unsaturated fatty acid to a more saturated one. Requires a metal catalyst (e.g., Ni):
Linoleic acid (18:2) + 2H₂ →(Ni)→ Stearic acid (18:0)
Industrial application: Partial hydrogenation of vegetable oils (e.g., corn oil, soybean oil) converts liquid polyunsaturated oils into solid or semi-solid fats (margarine). However, partial hydrogenation produces trans fatty acidsas a byproduct — these are associated with increased cardiovascular risk.
Acid Hydrolysis (Breakdown of Ester Bond)
Breaking the ester bond with water in the presence of a strong acid:
Ester + H₂O →(H⁺)→ Fatty acid + Alcohol
Saponification (Base Hydrolysis)
Breaking the ester bond with a strong base (e.g., NaOH):
Ester + NaOH → Fatty acid salt (soap) + Alcohol
The fatty acid salt (or soap) produced is a surfactant: it has a hydrophilic head (carboxylate –COO⁻Na⁺) and a hydrophobic tail, allowing it to emulsify fats in water.
6. Phospholipids
Phospholipids are characterized by having a phosphate group in their polar head. They are the primary structural components of biological membranes, contributing both structural integrity and functional signaling.
All phospholipids share:
- A backbone molecule (glycerol or sphingosine)
- Fatty acid chains (hydrophobic tails)
- A phosphate group connecting the backbone to a polar head group (an amino alcohol)
→ This gives phospholipids their amphipathic nature: one end is hydrophilic (polar), and the other is hydrophobic (nonpolar).
Two major subtypes:
- Glycerophospholipids — backbone is glycerol
- Sphingophospholipids — backbone is sphingosine
6.1 Glycerophospholipids
These are the most abundant lipids in cell membranes.
General Structure
O
‖
sn-1: CH₂–O–C–[Saturated fatty acid, e.g., palmitic acid]
O
‖
sn-2: CH–O–C–[Unsaturated fatty acid, e.g., oleic acid]
sn-3: CH₂–O–P–O–X
|
O⁻
Where X is the head-group alcohol (the variable polar component).
The phosphate group is esterified with another alcohol (X), which determines the name and charge of the specific glycerophospholipid.
Major Classes of Glycerophospholipids
| Name | Head Group (X) | Formula of X | Net Charge (pH 7) |
|---|---|---|---|
| Phosphatidic acid | — (H) | –H | −1 |
| Phosphatidylethanolamine (PE) | Ethanolamine | –CH₂–CH₂–NH₃⁺ | 0 |
| Phosphatidylcholine (PC) | Choline | –CH₂–CH₂–N⁺(CH₃)₃ | 0 |
| Phosphatidylserine (PS) | Serine | –CH(NH₃⁺)–COO⁻ | −1 |
| Phosphatidylglycerol (PG) | Glycerol | –CH₂–CHOH–CH₂OH | −1 |
| Phosphatidylinositol 4,5-bisphosphate (PIP₂) | myo-Inositol-4,5-bisphosphate | (cyclic hexitol) | −4 |
| Cardiolipin | Phosphatidylglycerol | (double phospholipid) | −2 |
Functional note: Phosphatidylinositol 4,5-bisphosphate (PIP₂) is a key signaling molecule. When cleaved by phospholipase C, it generates two second messengers: IP₃ (triggers Ca²⁺ release) and DAG (activates protein kinase C). This is the basis of the PI3K/Akt pathway mentioned in the slides.
Cardiolipin is unique: it is essentially two phosphatidic acids linked by a glycerol. It is found almost exclusively in the inner mitochondrial membrane, where it plays an important role in oxidative phosphorylation.
Galactolipids and Sulphatides
Other glycerides that do not contain phosphate but instead have sugars as their head groups:
- Galactolipids and sulphatides are found in plant cell membranes (especially chloroplasts).
6.2 Sphingolipids
Sphingolipids are structurally similar to phosphoglycerides but their backbone is sphingosine rather than glycerol.
Sphingosine = an unsaturated 18-carbon amino alcohol:
HO–CH(C1)–CH(C2)(NH₂)–CH=CH–(CH₂)₁₂–CH₃
The C-1, C-2, C-3 arrangement of sphingosine “resembles” glycerol functionally:
- C-1 (–OH): esterified with a phosphocholine or sugar group
- C-2 (–NH₂): forms an amide bond with a fatty acid (usually saturated) → this unit is called ceramide
- C-3: has a long hydrocarbon chain (part of sphingosine itself — no addition needed)
General Sphingolipid Structure
Sphingosine (18C amino alcohol)
+ Fatty acid (amide bond at C-2) → CERAMIDE
+ Variable head group at C-1 → different sphingolipid classes
Classes of Sphingolipids
| Name | Head Group | Notes |
|---|---|---|
| Ceramide | –H | Simplest sphingolipid; no polar head; also a signaling molecule (apoptosis) |
| Sphingomyelin | Phosphocholine or phosphoethanolamine | Only sphingolipid that is also a phospholipid |
| Glucosylcerebroside | Glucose | Glycosphingolipid (glycolipid) |
| Lactosylceramide (globoside) | Di-, tri-, or tetrasaccharide | Glycosphingolipid |
| Ganglioside GM2 | Complex oligosaccharide containing sialic acid | Important in neural tissue; accumulates in Tay-Sachs disease |
Sphingomyelins (Key Example)
Sphingomyelins are the only sphingolipids that are also phospholipids (they contain phosphate).
Structure: ceramide + phosphocholine (or phosphoethanolamine) at C-1
- Found in abundance in the myelin sheath surrounding axons in the central nervous system → essential for efficient nerve impulse conduction
- Sphingo-phospholipids are generally more saturated than glycerophospholipids
- More abundant in nervous system cells
Glycolipids and Blood Groups
Sphingolipids can act as cell surface antigens. The ABO blood group system is determined by the sugar residues on sphingolipids (specifically glycolipids) on the surface of red blood cells (erythrocytes):
- Type A: gene encodes an enzyme transferring N-acetylgalactosamine to the sphingolipid → antigen A
- Type B: gene encodes an enzyme transferring galactose → antigen B
- Type AB: both enzymes present → both antigens
- Type O: neither functional enzyme → no specific antigen (just the H antigen)
6.3 Role in Cell Membranes and Membrane Fluidity
Amphipathic Nature and the Lipid Bilayer
Phospholipids are amphipathic molecules: they have a hydrophilic polar head and a hydrophobic nonpolar tail (two fatty acid chains).
In aqueous environments, this causes phospholipids to spontaneously self-assemble into structures that minimize contact between the hydrophobic tails and water:
- Micelles: single-layered spheres, with tails inside and heads outside
- Lipid bilayer: two-layered sheet; tails face inward, heads face outward into water
The lipid bilayer is the structural basis of all cell membranes. It forms a two-dimensional “solvent” in which membrane proteins float (the fluid mosaic model).
Simplified depiction:
Extracellular space (aqueous)
○○○○○○○○○○○○○○ ← hydrophilic polar heads
|||||||||||||||| ← hydrophobic fatty acid tails
|||||||||||||||| ← hydrophobic fatty acid tails
○○○○○○○○○○○○○○ ← hydrophilic polar heads
Cytoplasm (aqueous)
Membrane Fluidity
Membrane fluidity is critical for:
- Proper protein function (receptors, transporters, enzymes)
- Membrane permeability
- Cell signaling
Factors that affect fluidity:
| Factor | Effect on Fluidity |
|---|---|
| ↑ Proportion of unsaturated FA (cis double bonds) | ↑ Fluidity ↑ Permeability |
| ↑ Proportion of saturated FA | ↓ Fluidity ↓ Permeability |
| Shorter chain length | ↑ Fluidity |
| Cholesterol (see Section 8.3) | Modulates fluidity depending on temperature |
BIOLOGICAL CONSEQUENCE: The composition of fatty acids in membrane phospholipidsdetermines membrane fluidity and, therefore, the proper function of membrane-bound proteins and the cell as a whole. This is why the balance of saturated vs. unsaturated fatty acids in the diet has such broad physiological effects.
7. Waxes
Waxes are esters formed from a fatty acid and a high molecular weight (long-chain) alcohol — NOT glycerol.
General reaction:
R–COOH + HO–R' → R–COO–R' + H₂O
(fatty acid) (long-chain alcohol) (wax)
Structural features:
- The fatty acid component: C14–C36
- The alcohol component: C16–C30 chain alcohols
- Both components are long, saturated or unsaturated straight chains
Physical properties:
- High melting points (60–100°C) → solid at room temperature due to high molar mass and extensive van der Waals interactions
- Completely insoluble in water (extremely hydrophobic)
Biological and industrial functions:
| Wax | Source/Use |
|---|---|
| Beeswax | Produced by honeybees to build honeycomb cells; major component is palmitic acid ester |
| Plant surface waxes | Cover the epidermis of leaves and fruits to prevent water loss (waterproofing) |
| Lanolin | Found in sheep’s wool; protective coating for hair and skin; used in skin creams and surfactants |
| Carnauba wax | From palm leaves; used in car polish |
8. Steroids and Cholesterol
8.1 Terpenes and the Isoprene Unit
Steroids are members of a large, diverse class of lipids called isoprenoids (terpenes), built from one or more 5-carbon isoprene units.
Isoprene (IUPAC: 2-methyl-1,3-butadiene):
CH₂=C(CH₃)–CH=CH₂
Terpenes built from isoprene units include:
- Steroid hormones (estrogens, testosterone, cortisol)
- Lipid-soluble vitamins (A, D, E, K)
- Chlorophyll and carotenoid pigments (photosynthesis)
- β-carotene — precursor to vitamin A
All steroids share the steroid nucleus: a characteristic fused ring system of three six-membered rings (A, B, C) and one five-membered ring (D) — containing 17 carbon atoms in the core.
CH₃
|
A B C D
[6C]–[6C]–[6C]–[5C] ← steroid carbon skeleton (17C core)
Vitamin A (Retinol)
- Derived from β-carotene (a terpene/carotenoid)
- Retinol can penetrate skin layers and stimulate collagen and elastin formation
- 11-cis-retinal (a derivative of retinol) is essential for vision under low-light conditions — it is the chromophore in the rod photoreceptors of the retina
8.2 Cholesterol: Structure and Properties
Cholesterol is the most important steroid in the human body. Its structure consists of:
- The 4-ring steroid nucleus (rigid, planar, hydrophobic)
- An 8-carbon branched hydrocarbon tail at C-17 (hydrophobic)
- A single hydroxyl group (–OH) at C-3 (hydrophilic)
This makes cholesterol amphipathic, though predominantly hydrophobic.
Two forms:
- Free cholesterol: has the –OH group → amphipathic; found in membranes
- Cholesteryl ester: –OH is esterified with a fatty acid → completely nonpolar, hydrophobic → stored in lipid droplets or carried in lipoprotein cores
8.3 Cholesterol: Functions
Cholesterol serves multiple vital roles:
-
Essential membrane component: Regulates membrane fluidity:
- At high or medium temperatures: reduces fluidity (the rigid planar ring constrains motion of fatty acid chains)
- At low temperatures: increases fluidity (prevents crystallization of fatty acid chains)
- Limits movement of unsaturated FA chains
- Makes long saturated FA chains more fluid
-
Precursor of bile acids (cholate and chenodeoxycholate):
- Synthesized in the liver, stored in the gallbladder
- Released into the small intestine, where they act as emulsifying agents to solubilize dietary lipids → essential for fat absorption
-
Precursor of steroid sex hormones:
- Progesterone — hormone of pregnancy
- Testosterone — male sex hormone (testes)
- Estrogens — female sex hormones
-
Precursor of corticosteroid hormones:
- Aldosterone — regulates blood sodium levels (mineralocorticoid)
- Cortisone — promotes glycogen synthesis and gluconeogenesis; inhibits inflammatory responses (glucocorticoid)
-
Precursor of Vitamin D:
- 7-dehydrocholesterol in the epidermis is converted to cholecalciferol (Vitamin D₃) upon exposure to UV light (sunlight)
8.4 Cholesterol Biosynthesis
Cholesterol comes from two sources:
- Dietary intake (~350 mg/day) — from eggs, dairy, meat
- De novo synthesis (~700 mg/day) — primarily in the liver (~50% of total), but also in intestine, adrenal cortex, and other nucleated cells
Biosynthetic pathway (simplified):
Acetyl-CoA
↓
Acetoacetyl-CoA
↓
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA)
↓ ← HMG-CoA Reductase (rate-limiting step)
↓ ← ★ INHIBITED BY STATINS ★
Mevalonate
↓
Squalene (30C terpene)
↓
Cholesterol
Clinical pharmacology: Statins (e.g., atorvastatin, simvastatin) are among the most widely prescribed drugs in the world. They inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, thereby reducing hepatic cholesterol production and lowering circulating LDL levels.
Synthesis occurs in the endoplasmic reticulum and cytosol of hepatocytes and other cells.
9. Plasma Lipoproteins
Because lipids are hydrophobic and essentially insoluble in blood (an aqueous medium), the body cannot transport free lipids efficiently. The solution is lipoproteins: specialized carrier particles.
Structure of Lipoproteins
Lipoprotein particles are spherical structures with:
- A hydrophobic core: rich in triglycerides and cholesteryl esters (nonpolar lipids)
- An amphipathic outer shell: made of phospholipids (polar heads outward), free cholesterol, and apolipoproteins(proteins that stabilize the particle and interact with receptors)
Think of a lipoprotein as a molecular “soap bubble” — the amphipathic shell keeps the hydrophobic core dissolved in plasma.
The Four Major Classes of Plasma Lipoproteins
Classified by density (determined by ultracentrifugation) — denser particles contain more protein and less lipid:
| Lipoprotein | Density | Size | Main Lipid Cargo | Key Apolipoproteins | Origin | Destination |
|---|---|---|---|---|---|---|
| Chylomicron | Lowest (lightest) | Largest (~100 nm) | Dietary TG (80–90%) | ApoB-48, ApoC, ApoE | Intestine | Peripheral tissues → liver |
| VLDL (Very Low Density) | Low | Large (~60 nm) | TG (endogenous, ~50%) | ApoB-100, ApoC, ApoE | Liver | Peripheral tissues |
| LDL (Low Density) | Medium | Medium (~25 nm) | Cholesterol + cholesteryl esters (~50%) | ApoB-100 | Derived from VLDL | Peripheral cells |
| HDL (High Density) | Highest (heaviest) | Smallest (~12 nm) | Cholesterol (~20%), phospholipids | ApoA-I | Liver/intestine | Peripheral tissues → liver |
9.1 Chylomicrons
- Formed in intestinal epithelial cells after absorption of dietary fats
- Transport dietary (exogenous) triglycerides and cholesterol from the gut to the rest of the body via the lymphatic system → bloodstream
- Lipoprotein lipase (LPL) in capillary walls cleaves TG → free fatty acids + glycerol
- Fatty acids → taken up by adipose tissue (storage) or muscle (energy)
- Remnant particles (depleted of TG) → taken up by the liver
9.2 VLDL
- Synthesized and secreted by the liver
- Transport endogenously synthesized triglycerides from the liver to peripheral tissues (adipose, muscle)
- As TG are delivered to tissues (via LPL), VLDL shrinks progressively → becomes IDL → then LDL
9.3 LDL (Bad Cholesterol)
- The end product of VLDL metabolism
- Richest lipoprotein in cholesterol (~50% of weight)
- Delivers cholesterol to peripheral tissues via LDL receptor (ApoB-100 interacts with receptor)
- In excess, LDL deposits cholesterol in arterial walls → atherosclerotic plaques → cardiovascular disease
“Bad cholesterol” label reflects the fact that elevated LDL is a major risk factor for coronary artery disease, stroke, and peripheral vascular disease.
9.4 HDL (Good Cholesterol)
- Synthesized in the liver and intestine
- Performs reverse cholesterol transport: picks up excess cholesterol from peripheral tissues (including arterial walls) and delivers it to the liver for disposal (as bile acids or excretion)
- Thus, HDL is cardioprotective — higher HDL levels are associated with lower cardiovascular risk
“Good cholesterol” label reflects its role in removing cholesterol from arteries. Think of HDL as a “cholesterol scavenger.”
The LDL/HDL Dynamic in Atherosclerosis:
Excess LDL → Deposits in artery wall → Oxidized LDL → Inflammation → Foam cells
→ Atherosclerotic plaque → Stenosis → Heart attack / Stroke
HDL → Removes cholesterol from plaque → Delivers to liver → Excreted as bile
→ Cardioprotective effect
9.5 Fat Digestion and Absorption
Dietary fat digestion involves several steps:
-
Emulsification by bile salts (in the small intestine):
- Large fat droplets are broken into small micelles by bile salts (amphipathic molecules derived from cholesterol)
- Greatly increases surface area for enzyme action
-
Enzymatic digestion by pancreatic lipase:
- Cleaves ester bonds in triglycerides → monoglycerides + free fatty acids (and some glycerol)
-
Absorption by intestinal epithelial cells:
- Short- and medium-chain fatty acids and glycerol → directly absorbed into the portal blood (capillary) due to their small size
- Long-chain fatty acids and monoglycerides → enter epithelial cells, are reassembled into triglycerides, packaged into chylomicrons within the Golgi apparatus, and secreted into lymphatic vessels (lacteals)
-
Transport via lymphatics:
- Chylomicrons travel through lymphatic channels → enter bloodstream via the thoracic duct
-
Delivery to tissues:
- Lipoprotein lipase (LPL) on capillary walls hydrolyzes chylomicron TG → fatty acids taken up by adipose (for storage) or muscle (for energy)
10. Clinical Relevance: Lifestyle and Lipid Levels
The management of dyslipidemia (abnormal lipid levels) is a key strategy for reducing cardiovascular risk. The European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS) guidelines identify the following interventions with their levels of evidence:
To Reduce TC and LDL-C (Total and Low-Density Lipoprotein Cholesterol)
| Intervention | Evidence Level |
|---|---|
| ↓ Dietary saturated fat | Strong (A) |
| ↑ Dietary fiber | Strong (A) |
| ↓ Dietary cholesterol | Moderate |
| Use phytosterol-enriched functional foods | Strong |
| ↓ Excess body weight | Moderate |
| Soy protein products | Moderate |
| ↑ Habitual physical activity | Moderate |
| Red yeast rice supplements | Moderate |
| Polycosanol supplements | Not effective |
To Reduce Triglycerides (TG)
| Intervention | Evidence Level |
|---|---|
| ↓ Excess body weight | Very strong |
| ↓ Alcohol intake | Very strong |
| ↓ Mono- and disaccharides (simple sugars) | Very strong |
| ↑ Habitual physical activity | Strong |
| ↓ Total dietary carbohydrate | Strong |
| n-3 PUFA supplements | Strong |
| Replace saturated fat with mono-/polyunsaturated fat | Moderate |
To Increase HDL-C
| Intervention | Evidence Level |
|---|---|
| ↓ Dietary trans fat | Very strong |
| ↑ Habitual physical activity | Very strong |
| ↓ Excess body weight | Strong |
| ↓ Dietary carbohydrates → replace with unsaturated fat | Strong |
| Moderate alcohol use | Strong |
| Quit smoking | Moderate |
| Prefer low-glycaemic-index, high-fibre carbohydrates | Moderate |
11. Summary and Conclusion
Lipids are a chemically diverse group of biomolecules unified by their hydrophobicity. This lesson has covered their major types, structures, and biological roles:
Key Takeaways by Section
Fatty Acids:
- Building blocks for most lipids
- Classified by chain length and degree of unsaturation
- Cis double bonds lower melting point and increase membrane fluidity
- Essential fatty acids (LA, ALA) must come from diet; they give rise to eicosanoids
- ω-3 → anti-inflammatory eicosanoids; ω-6 → pro-inflammatory eicosanoids
Glycerides (Triglycerides):
- Major energy storage form in adipocytes
- Density of ~120,000 kcal in a lean 70 kg person — primary long-term energy reservoir
- Mobilized by lipases; fatty acids transported by albumin to liver for β-oxidation
Phospholipids:
- Amphipathic → spontaneously form bilayers
- Glycerophospholipids (PC, PE, PS, PI) and sphingolipids (sphingomyelin) are the main membrane components
- Membrane composition (especially saturation of FA) determines fluidity → critical for protein function
- Sphingolipids also function in cell recognition (blood groups) and signaling (ceramide, gangliosides)
Cholesterol and Steroids:
- Modulates membrane fluidity
- Precursor of bile acids, sex hormones, corticosteroids, Vitamin D
- Synthesized mainly in liver via HMG-CoA reductase (target of statins)
- Diet provides roughly half of daily cholesterol; the rest is synthesized
Lipoproteins:
- Necessary for aqueous transport of hydrophobic lipids in blood
- Chylomicrons → dietary fat distribution
- VLDL → endogenous TG from liver to tissues
- LDL → cholesterol delivery to tissues; atherosclerosis risk when elevated
- HDL → reverse cholesterol transport; cardioprotective
Clinical Relevance:
- Diet rich in ω-3 PUFA, monounsaturated fats (EVOO), fiber and low in saturated and trans fats → reduced CVD risk
- Physical activity consistently improves lipid profiles across all parameters
- Statins inhibit cholesterol synthesis (HMG-CoA reductase) and are a cornerstone of dyslipidemia pharmacotherapy
- Aspirin inhibits cyclooxygenase → blocks thromboxane A₂-mediated platelet aggregation → antiplatelet therapy
Glossary of Key Terms
| Term | Definition |
|---|---|
| Amphipathic | Having both hydrophilic and hydrophobic regions |
| Eicosanoids | Hormone-like signaling molecules derived from 20-carbon fatty acids (PUFAs) |
| Ceramide | Sphingosine + fatty acid (via amide bond); core of all sphingolipids; signaling molecule in apoptosis |
| Saponification | Alkaline hydrolysis of an ester → soap (fatty acid salt) + alcohol |
| Lipoprotein lipase (LPL) | Enzyme on capillary walls that hydrolyzes TG in circulating lipoproteins |
| Apolipoprotein | Protein component of lipoproteins; determines receptor binding and metabolic fate |
| HMG-CoA reductase | Rate-limiting enzyme in cholesterol biosynthesis; target of statins |
| β-oxidation | Mitochondrial metabolic pathway that degrades fatty acids to acetyl-CoA for ATP production |
| Adipocyte | Fat cell specialized for triglyceride storage |
| Myelin sheath | Protective lipid-rich (sphingomyelin) insulating layer around axons in the CNS/PNS |
Last updated: March 2026 | Prepared for General Biochemistry | Università di Bologna – Medicina e Chirurgia