Biochemistry chapters
Fatty acids, lipoproteins and cholesterol
How fats are digested and carried (micelles, chylomicrons and the other lipoproteins), how fatty acids are made and burned (acetyl-CoA carboxylase, carnitine shuttle, beta-oxidation), how cholesterol is made and controlled (HMG-CoA reductase, LDL receptors), the hyperlipoproteinaemias and lipid storage diseases, and the ATP yield of palmitate worked out by hand.
- Dietary fat is emulsified by bile salts, digested by pancreatic lipase, absorbed in micelles, re-formed into triglycerides and exported in chylomicrons (apo B-48); lipoprotein lipase (activated by apo C-II) releases fatty acids from chylomicrons and VLDL (from liver, apo B-100), which becomes IDL and LDL (delivers cholesterol via LDL receptors); HDL carries cholesterol back to the liver (reverse cholesterol transport, LCAT).
- Fatty acid synthesis (cytosol, liver, fed state): rate-limiting acetyl-CoA carboxylase (biotin; activated by insulin and citrate) makes malonyl-CoA, which blocks CPT I so new fat is not burned; β-oxidation (mitochondria, fasting) needs the carnitine shuttle (CPT I rate-limiting) and yields acetyl-CoA, NADH and FADH₂; MCAD deficiency causes hypoketotic hypoglycaemia with fasting.
- Cholesterol synthesis: rate-limiting HMG-CoA reductase (inhibited by statins and cholesterol, activated by insulin); familial hypercholesterolaemia (LDL receptor defect, autosomal dominant) causes very high LDL, tendon xanthomas and early heart disease; Tay-Sachs (hexosaminidase A), Gaucher (glucocerebrosidase, the commonest) and Niemann-Pick (sphingomyelinase) are lysosomal sphingolipidoses.
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Lipids in brief
- Triglycerides (triacylglycerols): glycerol + 3 fatty acids; the main energy store (9 kcal/g).
- Fatty acids: saturated or unsaturated. Essential fatty acids (cannot be made): linoleic (ω-6) and α-linolenic (ω-3); arachidonic acid must come from the diet when linoleic acid is short. Deficiency: scaly dermatitis, poor growth.
- Phospholipids: membranes; dipalmitoyl phosphatidylcholine (lecithin) is the main lung surfactant (lecithin:sphingomyelin ratio above 2 in amniotic fluid suggests mature fetal lungs).
- Cholesterol: membranes, bile acids, steroid hormones, vitamin D.
Digestion and absorption
- Bile salts emulsify fat in the duodenum.
- Pancreatic lipase (with colipase) splits triglycerides into 2-monoacylglycerol and fatty acids.
- Products form mixed micelles with bile salts and are absorbed in the jejunum; bile salts are reabsorbed in the terminal ileum (enterohepatic circulation).
- In enterocytes, triglycerides are re-made and packed into chylomicrons (with apo B-48) → lymphatics (lacteals) → thoracic duct → blood.
- Short- and medium-chain fatty acids go directly to the portal blood (useful in malabsorption: MCT oil).
Steatorrhoea follows lack of bile (obstructive jaundice, ileal resection), lack of lipase (chronic pancreatitis, cystic fibrosis), or mucosal disease (coeliac disease); it brings deficiency of fat-soluble vitamins.
Lipoproteins
| Lipoprotein | Made in | Main lipid | Main apoproteins | Function |
|---|---|---|---|---|
| Chylomicrons | Intestine | Dietary triglyceride | B-48, C-II, E | Carry dietary fat to tissues; remnants taken up by liver (apo E) |
| VLDL | Liver | Endogenous triglyceride | B-100, C-II, E | Carry liver-made fat to tissues |
| IDL | From VLDL | Triglyceride and cholesterol | B-100, E | Become LDL or are taken by liver |
| LDL | From IDL | Cholesterol (richest) | B-100 | Deliver cholesterol to tissues via LDL receptor; atherogenic ("bad") |
| HDL | Liver and intestine | Phospholipid, cholesterol | A-I, C, E | Reverse cholesterol transport (tissues → liver); donates apo C-II and E; protective ("good") |
Density rises and size falls from chylomicrons (largest, least dense) to HDL (smallest, densest). On electrophoresis, LDL is β, VLDL pre-β, HDL α, and chylomicrons stay at the origin.
Key enzymes and proteins:
- Lipoprotein lipase (capillary endothelium of muscle and fat): hydrolyses triglycerides in chylomicrons and VLDL; activated by apo C-II; insulin increases it; released by heparin.
- Hormone-sensitive lipase (adipocytes): breaks down stored fat during fasting; activated by glucagon and adrenaline, inhibited by insulin.
- LCAT (lecithin-cholesterol acyltransferase, activated by apo A-I): esterifies cholesterol in HDL.
- CETP: moves cholesteryl esters from HDL to VLDL/LDL.
- Apo E: remnant uptake by the liver (apo E4: Alzheimer risk; apo E2 homozygosity: dysbetalipoproteinaemia).
Fatty acid synthesis
Location: cytosol, mainly liver, adipose tissue and lactating breast, in the fed state (insulin).
- Acetyl-CoA made in mitochondria leaves as citrate (citrate shuttle), then is split by ATP-citrate lyase.
- Acetyl-CoA carboxylase (the controlling, rate-limiting step; requires biotin and ATP) → malonyl-CoA. Activated by insulin (dephosphorylation) and citrate; inhibited by glucagon, adrenaline and long-chain acyl-CoA.
- Fatty acid synthase (multi-enzyme complex) adds 2 carbons at a time using NADPH; product: palmitate (16 carbons).
NADPH comes from the pentose phosphate pathway and malic enzyme.
Elongation and desaturation occur in the ER; humans cannot add double bonds beyond carbon 9 (hence essential fatty acids).
Fatty acid oxidation (β-oxidation)
Location: mitochondrial matrix, in the fasting state (glucagon). Very long-chain fatty acids start in peroxisomes.
- Activation in the cytosol: fatty acid → fatty acyl-CoA (uses ATP → AMP: 2 high-energy bonds).
- Carnitine shuttle: carnitine palmitoyltransferase I (CPT I) on the outer mitochondrial membrane (rate-limiting; inhibited by malonyl-CoA) → acylcarnitine crosses → CPT II reforms acyl-CoA inside.
- β-oxidation cycle: each turn removes 2 carbons as acetyl-CoA and makes 1 FADH₂ + 1 NADH.
Odd-chain fatty acids leave propionyl-CoA → methylmalonyl-CoA (biotin) → succinyl-CoA (needs B12): the only part of fat that can become glucose.
Malonyl-CoA (from synthesis) blocks CPT I, so fatty acids are not made and burned at the same time.
Turns of β-oxidation = (16 ÷ 2) − 1 = 7
Acetyl-CoA formed = 16 ÷ 2 = 8
7 FADH₂ × 1.5 = 10.5 ATP
7 NADH × 2.5 = 17.5 ATP
8 acetyl-CoA × 10 (TCA) = 80 ATP
Total = 10.5 + 17.5 + 80 = 108 ATP
Minus activation (2 high-energy bonds) = 108 − 2 = 106 ATP
(Older values of 3 and 2 give 129 net.)
Compare glucose (6 C) about 32 ATP: per carbon, fat yields more.
Disorders of fatty acid oxidation
- MCAD deficiency (medium-chain acyl-CoA dehydrogenase): the commonest; presents with fasting or illness: hypoketotic hypoglycaemia, vomiting, lethargy, liver dysfunction, sudden infant death; raised dicarboxylic acids and octanoylcarnitine. Avoid fasting.
- Carnitine deficiency / CPT I or II deficiency: hypoketotic hypoglycaemia, muscle weakness, myoglobinuria with exercise (CPT II), cardiomyopathy. Carnitine deficiency also occurs with valproate and dialysis.
- Jamaican vomiting sickness (unripe ackee: hypoglycin) blocks acyl-CoA dehydrogenases.
- Zellweger syndrome: peroxisome defect; very long-chain fatty acids build up; hypotonia, seizures, liver disease.
- Refsum disease: phytanic acid (α-oxidation in peroxisomes).
Cholesterol
Synthesis
Location: cytosol and ER, mainly liver; from acetyl-CoA.
Acetyl-CoA → HMG-CoA → (HMG-CoA reductase: rate-limiting, needs NADPH) → mevalonate → isoprenoids → squalene → lanosterol → cholesterol.
HMG-CoA reductase is:
- Inhibited by cholesterol (feedback; also stimulates its breakdown), statins (competitive inhibitors), glucagon.
- Stimulated by insulin and thyroid hormone.
Statins lower liver cholesterol → more LDL receptors made → LDL cleared from blood.
Fate of cholesterol
- Bile acids (main route of elimination; rate-limiting 7α-hydroxylase, needs vitamin C), conjugated with glycine or taurine.
- Steroid hormones (adrenal cortex, gonads, placenta).
- Vitamin D (from 7-dehydrocholesterol in skin).
- Membranes; excreted unchanged in bile (excess → gallstones).
Disorders of lipoproteins
Fredrickson classification
| Type | Raised lipoprotein | Defect | Features |
|---|---|---|---|
| I | Chylomicrons | Lipoprotein lipase or apo C-II deficiency | Very high triglycerides, acute pancreatitis, eruptive xanthomas, lipaemia retinalis, hepatosplenomegaly; no extra heart disease |
| IIa | LDL | LDL receptor (familial hypercholesterolaemia) | High cholesterol, tendon xanthomas (Achilles), xanthelasma, corneal arcus, early coronary disease |
| IIb | LDL + VLDL | Combined hyperlipidaemia | Common; heart disease |
| III | IDL / remnants | Apo E2 homozygosity | Palmar xanthomas, tuberoeruptive xanthomas |
| IV | VLDL | Overproduction (often with diabetes, alcohol, obesity) | Raised triglycerides; pancreatitis risk |
| V | VLDL + chylomicrons | Mixed | Pancreatitis |
Familial hypercholesterolaemia: autosomal dominant; heterozygotes (cholesterol roughly doubled, heart attacks in their 40s–50s) are fairly common; homozygotes (very high levels, heart attacks in childhood) are rare. Treat with statins, ezetimibe, PCSK9 inhibitors.
Secondary hyperlipidaemia: diabetes, hypothyroidism, nephrotic syndrome, obstructive jaundice, alcohol, obesity, drugs (thiazides, steroids, retinoids, antiretrovirals).
Abetalipoproteinaemia: defect in MTP (microsomal triglyceride transfer protein) → no apo B-containing lipoproteins (no chylomicrons, VLDL, LDL): fat malabsorption, steatorrhoea, acanthocytes, fat-soluble vitamin deficiency (especially vitamin E: ataxia, retinitis pigmentosa).
Sphingolipidoses (lysosomal storage diseases)
| Disease | Enzyme | Stored | Features | Inheritance |
|---|---|---|---|---|
| Gaucher | Glucocerebrosidase | Glucocerebroside | The commonest; hepatosplenomegaly, bone pain and crises, pancytopenia; Gaucher cells (macrophages with "crumpled tissue paper" cytoplasm); enzyme replacement | AR |
| Tay-Sachs | Hexosaminidase A | GM2 ganglioside | Progressive neurodegeneration, exaggerated startle, cherry-red macula, no hepatosplenomegaly; onion-skin lysosomes | AR |
| Niemann-Pick | Sphingomyelinase | Sphingomyelin | Neurodegeneration, hepatosplenomegaly, cherry-red macula, foam cells | AR |
| Fabry | α-galactosidase A | Ceramide trihexoside | Burning pain in hands and feet, angiokeratomas, hypohidrosis, kidney failure, heart disease, stroke | X-linked |
| Krabbe | Galactocerebrosidase | Galactocerebroside | Neurodegeneration, optic atrophy, globoid cells | AR |
| Metachromatic leukodystrophy | Arylsulfatase A | Sulfatides | Central and peripheral demyelination | AR |
Cherry-red spot: Tay-Sachs (no organomegaly) and Niemann-Pick (with hepatosplenomegaly). Fabry is the only X-linked one in this list. Gaucher is the commonest.
Expect: fat digestion and micelles, lipoprotein types, sources and apoproteins (B-48, B-100, C-II, E, A-I), lipoprotein lipase and hormone-sensitive lipase regulation, LCAT and reverse cholesterol transport, rate-limiting enzymes of fatty acid synthesis (acetyl-CoA carboxylase), oxidation (CPT I) and cholesterol synthesis (HMG-CoA reductase), malonyl-CoA control, palmitate ATP yield, MCAD deficiency, odd-chain fatty acids and B12, statins and LDL receptors, Fredrickson types I and IIa, abetalipoproteinaemia, and the sphingolipidoses.
Quick revision
- Chylomicrons: dietary fat, B-48. VLDL: liver fat, B-100. LDL: cholesterol to tissues. HDL: back to liver.
- Apo C-II activates lipoprotein lipase; apo E for remnant uptake; LCAT (apo A-I) in HDL.
- Fatty acid synthesis: cytosol, acetyl-CoA carboxylase (biotin), NADPH.
- β-oxidation: mitochondria, CPT I (blocked by malonyl-CoA); palmitate ≈ 106 ATP.
- MCAD deficiency: hypoketotic hypoglycaemia on fasting.
- Cholesterol: HMG-CoA reductase (statins); bile acids via 7α-hydroxylase.
- FH: LDL receptor, tendon xanthomas. Type I: LPL/apo C-II, pancreatitis.
- Gaucher (commonest), Tay-Sachs (cherry-red, no organomegaly), Niemann-Pick, Fabry (X-linked).
Written by The House Job from standard biochemistry references (Lippincott Illustrated Reviews: Biochemistry).
FAQ
Which apolipoprotein activates lipoprotein lipase?
Apolipoprotein C-II.
Which enzyme controls the rate of fatty acid synthesis?
Acetyl-CoA carboxylase, which needs biotin and is activated by insulin and citrate.
How are newly made fatty acids kept from being oxidised?
Malonyl-CoA, the first product of fatty acid synthesis, inhibits carnitine palmitoyltransferase I, so fatty acids cannot enter mitochondria for oxidation.
Which receptor is defective in familial hypercholesterolaemia?
The LDL receptor.