Page 2 of 7

BI4.1-8 | Chemistry and Metabolism of Lipids — Part 1

Classification of Lipids — The Fat Family (BI4.1)

Lipids are a diverse group of biomolecules defined by one property: they are insoluble in water but soluble in organic solvents (chloroform, ether, benzene). Unlike carbohydrates and proteins, lipids are not defined by a common structural backbone — they are defined by their physical behaviour.

Figure: Classification of Lipids — The Fat Family (BI4.1)

Lipids are classified into three main groups:

1. Simple lipids — esters of fatty acids with alcohols:
• Fats and oils (triacylglycerols/triglycerides) — three fatty acids esterified to glycerol. Fats are solid at room temperature (saturated, e.g. ghee, butter); oils are liquid (unsaturated, e.g. groundnut oil, olive oil). Triglycerides are the body's primary energy store — stored in adipose tissue, providing ~9 kcal/g (more than double the energy density of carbohydrates at ~4 kcal/g).
• Waxes — esters of fatty acids with long-chain alcohols. Found in sebum (skin), cerumen (earwax), and the coating of leaves.

2. Compound (complex) lipids — contain an additional group beyond fatty acids and alcohol:
• Phospholipids — contain a phosphate group. The most important membrane lipids. Two subtypes: glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine — major components of cell membranes) and sphingophospholipids (sphingomyelin — abundant in the myelin sheath of nerves).
• Glycolipids — contain a sugar group. Cerebrosides (one sugar) and gangliosides (oligosaccharide with sialic acid) — abundant in brain and nervous tissue.
• Lipoproteins — lipids complexed with proteins for transport in blood (chylomicrons, VLDL, LDL, HDL — we'll cover these in Part 2).

3. Derived lipids — obtained by hydrolysis of simple or compound lipids:
• Fatty acids — the building blocks of most lipids
• Cholesterol — a sterol (steroid + alcohol). Precursor to bile acids, steroid hormones (cortisol, aldosterone, testosterone, oestrogen), and vitamin D.
• Prostaglandins, leukotrienes, thromboxanes — signalling molecules derived from arachidonic acid (a 20-carbon fatty acid). These mediate inflammation, pain, fever, and blood clotting.

Key concept: Lipids serve four major biological roles: (1) energy storage (triglycerides), (2) structural (phospholipids in membranes), (3) signalling (steroid hormones, prostaglandins), (4) insulation and protection (subcutaneous fat, myelin).

Fatty Acids — Saturated, Unsaturated, and Essential (BI4.2)

Fatty acids are long-chain carboxylic acids — a hydrocarbon chain with a carboxyl group (-COOH) at one end. They are the fundamental building blocks of most lipids.

Figure: Fatty Acids — Saturated, Unsaturated, and Essential (BI4.2)

Classification by saturation:
• Saturated fatty acids (SFA) — no double bonds in the carbon chain. The chain is 'saturated' with hydrogen atoms. They pack tightly together → solid at room temperature. Examples: palmitic acid (C16:0 — 16 carbons, 0 double bonds), stearic acid (C18:0). Found abundantly in ghee, butter, coconut oil.

• Monounsaturated fatty acids (MUFA) — one double bond (usually cis configuration, creating a 'kink' in the chain). Example: oleic acid (C18:1, Δ9 — 18 carbons, 1 double bond at position 9). Found in olive oil, groundnut oil, mustard oil. The kink prevents tight packing → liquid at room temperature.

• Polyunsaturated fatty acids (PUFA) — two or more double bonds. Examples: linoleic acid (C18:2, omega-6), linolenic acid (C18:3, omega-3), arachidonic acid (C20:4, omega-6). The more double bonds, the more fluid the molecule.

Essential fatty acids (EFAs):
Humans cannot synthesise double bonds beyond carbon 9 from the carboxyl end. Therefore, two fatty acids are essential (must come from diet):
• Linoleic acid (C18:2, omega-6) — found in sunflower oil, safflower oil, soybean oil
• α-Linolenic acid (C18:3, omega-3) — found in flaxseed, walnuts, fish oil

From linoleic acid, the body can synthesise arachidonic acid (the precursor to prostaglandins, thromboxanes, and leukotrienes). From α-linolenic acid, the body can (inefficiently) synthesise EPA and DHA — the omega-3 fatty acids in fish oil that are cardioprotective.

Omega numbering: The omega (ω) system counts from the methyl end (opposite to the carboxyl end). Omega-3 means the first double bond is 3 carbons from the methyl end. Omega-6 means 6 carbons from the methyl end. This is the system used in clinical nutrition.

Trans fatty acids: Industrial hydrogenation of vegetable oils creates trans double bonds (the hydrogen atoms are on opposite sides of the double bond, unlike the natural cis configuration). Trans fats behave like saturated fats — they raise LDL cholesterol and lower HDL cholesterol, increasing cardiovascular risk. The WHO has called for global elimination of industrial trans fats by 2023. Common sources in India: vanaspati ghee, bakery products, deep-fried street food.

Beta-Oxidation — Breaking Down Fat for Energy (BI4.3)

When you skip a meal or exercise intensely, your body shifts from burning glucose to burning fat. Beta-oxidation is the process by which fatty acids are broken down into acetyl-CoA units, which then enter the TCA cycle for energy generation.

Figure: Beta-Oxidation — Breaking Down Fat for Energy (BI4.3)

The process occurs in the mitochondrial matrix and has four repeating steps:

Step 0 — Activation (cytoplasm):
Before a fatty acid can enter the mitochondrion, it must be 'activated' by attaching to coenzyme A (CoA), forming acyl-CoA. This reaction requires 2 ATP (technically ATP → AMP + PPi, equivalent to 2 ATP) and is catalysed by acyl-CoA synthetase (also called fatty acid thiokinase).

The carnitine shuttle — getting the fatty acid across the mitochondrial membrane:
The inner mitochondrial membrane is impermeable to long-chain acyl-CoA. The fatty acid must be transferred to carnitine by CPT-I (carnitine palmitoyltransferase I, on the outer membrane), transported across as acylcarnitine by a translocase, and then transferred back to CoA by CPT-II (on the inner membrane). CPT-I is the rate-limiting step of beta-oxidation. It is inhibited by malonyl-CoA (the first committed intermediate of fatty acid synthesis) — this is how the body prevents simultaneous synthesis and breakdown of fatty acids.

The 4-step spiral (each cycle removes 2 carbons):

1. Oxidation (by acyl-CoA dehydrogenase) — removes 2H → produces FADH₂



Figure: The 4-step spiral (each cycle removes 2 carbons):

2. Hydration (by enoyl-CoA hydratase) — adds H₂O across the double bond
3. Oxidation (by 3-hydroxyacyl-CoA dehydrogenase) — removes 2H → produces NADH
4. Thiolysis (by β-ketothiolase) — cleaves off acetyl-CoA + a shortened acyl-CoA

The shortened acyl-CoA re-enters the spiral, losing 2 carbons each cycle.

Energy yield from palmitic acid (C16:0):
• 7 cycles of beta-oxidation → 8 acetyl-CoA + 7 FADH₂ + 7 NADH
• 8 acetyl-CoA → TCA cycle → 8 × 10 ATP = 80 ATP
• 7 FADH₂ → 7 × 1.5 = 10.5 ATP
• 7 NADH → 7 × 2.5 = 17.5 ATP
• Total = 108 ATP − 2 ATP (activation) = 106 net ATP

Compare this to glucose: 1 glucose (6C) yields ~30-32 ATP. 1 palmitate (16C) yields 106 ATP. Fat is a far more efficient energy store — this is why the body stores excess energy as fat, not glycogen.

Clinical connection — MCAD deficiency:
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of fatty acid oxidation. Affected children cannot oxidise medium-chain fatty acids → they develop hypoketotic hypoglycaemia during fasting (low blood sugar + no ketone bodies as backup). Newborn screening for MCAD deficiency is lifesaving — treatment is simply avoiding prolonged fasting.

Fatty Acid Synthesis (Lipogenesis) — Building Fat from Scratch (BI4.4)

When you eat more carbohydrates than you need, your body converts the excess into fat. This is lipogenesis — the synthesis of fatty acids from acetyl-CoA. It occurs in the cytoplasm (not the mitochondrion) of liver and adipose tissue.

Figure: Fatty Acid Synthesis (Lipogenesis) — Building Fat from Scratch (BI4.4)

Key differences from beta-oxidation:

Feature	Beta-oxidation	Lipogenesis
Location	Mitochondrial matrix	Cytoplasm
Carrier	CoA	ACP (acyl carrier protein)
2-carbon unit	Acetyl-CoA (released)	Malonyl-CoA (added)
Coenzyme	FAD, NAD⁺ (reduced)	NADPH (oxidised)
Enzyme	Multiple separate enzymes	Fatty acid synthase (single multi-enzyme complex)
Regulation	Activated by fasting	Activated by feeding

The pathway:

Figure: Key differences from beta-oxidation:

1. Acetyl-CoA must exit the mitochondrion — it does so as citrate (via the citrate shuttle: acetyl-CoA + OAA → citrate in mitochondrion, citrate crosses membrane, ATP-citrate lyase regenerates acetyl-CoA + OAA in cytoplasm).

2. Committed step: Acetyl-CoA → malonyl-CoA by acetyl-CoA carboxylase (ACC) — this is the rate-limiting enzyme of fatty acid synthesis. It requires biotin as a cofactor and is:
- Activated by: citrate, insulin (fed state)
- Inhibited by: palmitoyl-CoA (product feedback), glucagon/adrenaline (fasting/stress)

1. Fatty acid synthase (FAS) — a remarkable multi-enzyme complex that performs 7 sequential reactions, adding 2 carbons (from malonyl-CoA) per cycle. It uses NADPH as the reducing agent (supplied by the pentose phosphate pathway and the malic enzyme).

1. The product is palmitic acid (C16:0) — further elongation and desaturation occur in the endoplasmic reticulum.

Hormonal regulation — the fed vs fasting switch:
• Insulin (fed state): activates ACC → promotes lipogenesis → excess carbohydrate converted to fat
• Glucagon (fasting): inhibits ACC → blocks lipogenesis → fatty acids are oxidised instead

This is why a high-carbohydrate diet promotes weight gain: excess glucose → pyruvate → acetyl-CoA → citrate → cytoplasmic acetyl-CoA → malonyl-CoA → palmitate → triglycerides → stored in adipose tissue. The biochemistry explains the epidemic of obesity in India as diets shift to refined carbohydrates (white rice, maida, sugar).