Cholesterol Metabolism & Lipoprotein Disorders

Cholesterol homeostasis, the lipoprotein transport system, and their inherited derangements are among the highest-yield, most clinically integrated topics in NEET PG Biochemistry. Master the HMG-CoA reductase pathway, the four major lipoprotein classes with their signature apolipoproteins, and the Fredrickson dyslipidaemias — these recur every year, often as clinical vignettes linking biochemistry to cardiology and paediatrics.

Cholesterol structure and roles

Cholesterol is a 27-carbon sterol with a cyclopentanoperhydrophenanthrene ring, a 3-β hydroxyl group, a double bond between C5–C6, and an 8-carbon side chain. It is the precursor for:

• Bile acids (largest fate, ~50% of daily turnover)
• Steroid hormones (cortisol, aldosterone, sex steroids)
• Vitamin D (7-dehydrocholesterol → cholecalciferol in skin)
• Cell membranes (modulates fluidity; abundant in lipid rafts)

High-yield: Cholesterol cannot be catabolised to CO₂ and water by humans. It is eliminated only as bile acids/salts and free cholesterol in bile (and shed in faeces). This is why bile-acid sequestrants lower cholesterol.

Cholesterol biosynthesis (HMG-CoA reductase pathway)

Synthesis occurs in the cytosol and smooth endoplasmic reticulum of virtually all nucleated cells, principally the liver and intestine. The reducing power is NADPH (from the HMP shunt). All 27 carbons derive from acetyl-CoA.

Stepwise flow:

1. 2 Acetyl-CoA → Acetoacetyl-CoA (thiolase)
2. Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (HMG-CoA synthase) — cytosolic isoenzyme, distinct from the mitochondrial one used in ketogenesis
3. HMG-CoA → Mevalonate (HMG-CoA reductase, uses 2 NADPH) — RATE-LIMITING, committed step
4. Mevalonate → Isopentenyl pyrophosphate (IPP, "active isoprene") → Dimethylallyl-PP
5. Condensations → Geranyl-PP → Farnesyl-PP → Squalene (squalene synthase)
6. Squalene → Lanosterol (squalene monooxygenase, needs O₂ + NADPH) → Cholesterol (after ~19 steps)

High-yield: HMG-CoA reductase is the rate-limiting enzyme of cholesterol synthesis and the target of statins. It is an integral ER membrane protein.

Regulation of HMG-CoA reductase:

Mechanism	Effect	Detail
SREBP-2 (transcription)	Low cholesterol → ↑ enzyme	Sterol-regulatory element binding protein; activated when ER sterols are low (sensed by SCAP/INSIG)
Phosphorylation	AMPK phosphorylates → inactive	Energy depletion (high AMP) switches it off
Dephosphorylation	Insulin → active	Fed state favours synthesis
Sterol-accelerated degradation	High cholesterol → enzyme degraded	Proteolysis via INSIG
Drugs	Statins competitively inhibit	Statins resemble mevalonate; ↑ LDL-receptor expression secondarily

Mnemonic for the regulators: "Insulin In, Glucagon Goes off" — insulin (dephosphorylation) and thyroxine increase activity; glucagon and glucocorticoids decrease it.

Bile acid synthesis

The major route of cholesterol disposal. Occurs in hepatocytes.

• 7-α-hydroxylase (CYP7A1) is the rate-limiting enzyme; it requires vitamin C, O₂, NADPH and cytochrome P450.
• Primary bile acids: cholic acid and chenodeoxycholic acid, made in the liver.
• Conjugation with glycine or taurine → bile salts (more amphipathic, better emulsifiers); lowers pKa so they stay ionised.
• Gut bacteria deconjugate and dehydroxylate primaries → secondary bile acids: deoxycholic acid (from cholic) and lithocholic acid (from chenodeoxycholic).
• Enterohepatic circulation: ~95% reabsorbed in the terminal ileum (active transport) and returned to liver.

High-yield: Bile acids feedback-inhibit CYP7A1. Bile-acid sequestrants (cholestyramine) interrupt enterohepatic recirculation → ↑ CYP7A1 activity → more cholesterol consumed → ↑ hepatic LDL receptors → ↓ plasma LDL.

Lipoproteins — structure and classes

Lipoproteins are spherical particles with a hydrophobic core (triacylglycerol + cholesteryl esters) and an amphipathic shell (phospholipids, free cholesterol, apolipoproteins). Density rises and size falls as protein content rises.

Lipoprotein	Origin	Major lipid	Key apolipoproteins	Function
Chylomicron	Intestine	Dietary TAG	B-48, C-II, E, A	Transport dietary fat to tissues
VLDL	Liver	Endogenous TAG	B-100, C-II, E	Transport endogenous TAG from liver
IDL (remnant)	VLDL catabolism	TAG + cholesterol	B-100, E	Transient; → LDL or cleared by liver
LDL	IDL catabolism	Cholesteryl ester	B-100	Deliver cholesterol to peripheral tissues ("bad")
HDL	Liver & intestine	Cholesteryl ester	A-I, C, E	Reverse cholesterol transport ("good")

High-yield ordering: Density: HDL > LDL > IDL > VLDL > chylomicron. Size is the exact reverse. Electrophoretic mobility: chylomicrons stay at origin; VLDL = pre-β; LDL = β; HDL = α.

Apolipoproteins — must-know functions

Apo	Function / association
Apo B-48	Structural for chylomicrons (intestine); B-48 = 48% of B-100 (RNA editing)
Apo B-100	Structural for VLDL/IDL/LDL; ligand for the LDL receptor
Apo C-II	Activates lipoprotein lipase (LPL)
Apo C-III	Inhibits LPL
Apo A-I	Activates LCAT; structural for HDL
Apo E	Ligand for hepatic remnant (apo E) receptor; isoform E4 ↔ Alzheimer risk
Apo(a)	Lipoprotein(a) — independent atherogenic/thrombotic risk

Mnemonic: "C-II actiVates LPL" (II → activates; III → inhibits). "A-I Activates LCAT."

Lipoprotein metabolism pathways

Exogenous (dietary) pathway: Dietary fat → chylomicrons (apo B-48) → enter lymphatics → acquire C-II and E from HDL in blood → LPL (on capillary endothelium of muscle/adipose, activated by C-II) hydrolyses TAG → free fatty acids to tissues → chylomicron remnant returns C-II to HDL → remnant taken up by liver via apo E receptor.

Endogenous pathway: Liver packages TAG into VLDL (apo B-100) → LPL acts → VLDL → IDL → hepatic lipase + further delipidation → LDL → LDL taken up by peripheral cells and liver via LDL (apo B-100/E) receptor by receptor-mediated endocytosis.

Reverse cholesterol transport (HDL): Nascent discoidal HDL (apo A-I) → ABCA1 transporter effluxes free cholesterol from peripheral cells → LCAT (lecithin-cholesterol acyltransferase, activated by apo A-I) esterifies it → mature spherical HDL → cholesteryl esters delivered to liver directly (via SR-B1) or swapped to VLDL/LDL for TAG by CETP (cholesteryl ester transfer protein).

High-yield enzymes: LPL (capillary endothelium, C-II activated, hydrolyses circulating TAG) vs hormone-sensitive lipase (intracellular adipocyte, mobilises stored TAG, activated by adrenaline/glucagon, inhibited by insulin) vs LCAT (plasma, esterifies HDL cholesterol). Do not confuse them.

LDL receptor and the Brown–Goldstein pathway

LDL binds its receptor via apo B-100 → clathrin-coated pits → endocytosis → endosome → receptor recycles, LDL degraded in lysosome → free cholesterol released. Intracellular cholesterol then:

1. ↓ HMG-CoA reductase (less synthesis)
2. ↓ LDL receptor synthesis (less uptake)
3. ↑ ACAT (acyl-CoA cholesterol acyltransferase) → stores cholesterol as esters

High-yield: PCSK9 promotes degradation of the LDL receptor. Gain-of-function PCSK9 mutations → hypercholesterolaemia; PCSK9 inhibitors (alirocumab, evolocumab) ↑ LDL receptors → lower LDL dramatically.

Inherited lipoprotein disorders

Familial hypercholesterolaemia (Type IIa)

• Defect: LDL receptor (most common), or apo B-100, or gain-of-function PCSK9.
• Inheritance: Autosomal dominant.
• Heterozygous: LDL ~2× normal; tendon xanthomas (Achilles, extensor tendons), xanthelasma, corneal arcus, premature CAD (40s).
• Homozygous: LDL 4–6×; CAD/MI in childhood; planar/tuberous xanthomas. Statins less effective (few receptors); needs LDL apheresis, evolocumab, lomitapide, or liver transplant.

Fredrickson (WHO) classification of hyperlipoproteinaemias

Type	Elevated particle	Lipid raised	Defect	Clinical clue
I	Chylomicrons	TAG ↑↑↑	LPL or apo C-II deficiency	Eruptive xanthoma, lipaemia retinalis, pancreatitis; no ↑ CAD
IIa	LDL	Cholesterol ↑↑	LDL receptor / apo B-100	Tendon xanthoma, arcus, premature CAD
IIb	LDL + VLDL	Cholesterol + TAG	Hepatic overproduction apo B	Combined hyperlipidaemia
III	IDL (β-VLDL)	Both ↑	Apo E2/E2 (defective E)	Palmar (tuberoeruptive) xanthoma, dysbetalipoproteinaemia
IV	VLDL	TAG ↑↑	VLDL overproduction	Commonest; assoc. obesity/diabetes
V	Chylomicrons + VLDL	TAG ↑↑↑	Mixed	Pancreatitis risk

High-yield: Type I & V (chylomicron-rich, very high TAG) → acute pancreatitis is the danger, not atherosclerosis. Types II & III → premature atherosclerosis/CAD. Type III is uniquely linked to apo E2 homozygosity and palmar xanthomas.

Mnemonic for "which is chylomicron": "One = chylomicrons, lipoprotein lipase Lost" (Type I = LPL deficiency).

HDL/transport deficiencies

• Tangier disease: ABCA1 mutation → cannot efflux cholesterol to HDL → near-absent HDL, orange tonsils, hepatosplenomegaly, neuropathy, cholesterol-laden macrophages.
• LCAT deficiency: cannot esterify HDL cholesterol → corneal opacities ("fish-eye disease"), anaemia, proteinuria/renal failure.
• Abetalipoproteinaemia: MTP (microsomal triglyceride transfer protein) defect → cannot assemble apo-B lipoproteins → no chylomicrons/VLDL → fat malabsorption, acanthocytes, retinitis pigmentosa, ataxia (vit E deficiency), steatorrhoea.
• Familial hypertriglyceridaemia: VLDL overproduction; risk of pancreatitis when severe.

Clinical features (pattern recognition)

• Xanthelasma & corneal arcus: hypercholesterolaemia (esp. IIa).
• Tendon xanthomas (Achilles): familial hypercholesterolaemia — almost pathognomonic.
• Palmar xanthomas: Type III (dysbetalipoproteinaemia).
• Eruptive xanthomas + lipaemia retinalis: severe hypertriglyceridaemia (I, V).
• Orange tonsils: Tangier disease.

Diagnosis & investigations

• Fasting lipid profile (12–14 h): total cholesterol, LDL, HDL, TAG. Friedewald formula: LDL = TC − HDL − (TAG/5) [mg/dL]; invalid if TAG > 400 mg/dL or in type III.
• Standing plasma test: refrigerate overnight — a creamy supernatant = chylomicrons (type I/V); a turbid infranatant = VLDL (type IV).
• Lipoprotein electrophoresis / ultracentrifugation: classify Fredrickson type; "broad β band" = type III.
• Genetic testing / apo E genotyping for type III; PCSK9, LDLR sequencing for FH.
• Lp(a) and apo B for residual risk assessment.

Lipid (ATP III, mg/dL)	Optimal / Desirable	High / Risk
LDL	< 100	≥ 160 high; ≥ 190 very high
HDL	≥ 60 protective	< 40 (men) low/risk
Triglycerides	< 150	≥ 200 high; ≥ 500 pancreatitis risk
Total cholesterol	< 200	≥ 240 high

Management / drug of choice

Statins are the drug of choice for hypercholesterolaemia (LDL-driven).

Drug class	Mechanism	Main effect
Statins (atorvastatin, rosuvastatin)	Inhibit HMG-CoA reductase → ↑ LDL receptors	↓↓ LDL; myopathy, ↑ transaminases
Ezetimibe	Inhibits NPC1L1 intestinal cholesterol absorption	↓ LDL; synergy with statin
Bile-acid sequestrants (cholestyramine)	Interrupt enterohepatic bile-acid recycling	↓ LDL; may ↑ TAG
PCSK9 inhibitors (evolocumab, alirocumab)	Block PCSK9 → ↑ LDL receptors	↓↓↓ LDL (for FH, statin-intolerant)
Fibrates (fenofibrate)	PPAR-α agonist → ↑ LPL, ↓ apo C-III	↓↓ TAG — DOC for hypertriglyceridaemia
Niacin	↓ hepatic VLDL secretion, ↓ HSL	↓ TAG, ↑ HDL; flushing (PGD2)
Omega-3 / icosapent ethyl	↓ VLDL synthesis	↓ TAG
Inclisiran	siRNA against PCSK9 mRNA	↓ LDL, twice-yearly dosing
Bempedoic acid	Inhibits ATP-citrate lyase (upstream of HMG-CoA)	↓ LDL, less myopathy

High-yield drug pearls: Statin DOC for high LDL; fibrate DOC for high TAG; lomitapide (MTP inhibitor) and PCSK9 inhibitors for homozygous FH. Type I (LPL/apo C-II deficiency) does NOT respond to statins/fibrates — manage with a very low-fat diet. Niacin flushing is prostaglandin-mediated and blocked by aspirin.

Complications

• Premature atherosclerosis, CAD, stroke, peripheral arterial disease (types II, III; high LDL/Lp(a)).
• Acute pancreatitis when TAG > 1000 mg/dL (types I, V).
• Xanthomas (cosmetic, joint involvement with tendon disease).
• Aortic stenosis / supravalvular involvement in homozygous FH.
• Statin complications: myopathy/rhabdomyolysis (↑ CK), transaminitis, new-onset diabetes (small risk).

Key differentials

• Hypercholesterolaemia vs hypertriglyceridaemia: Tendon xanthoma + arcus + family CAD → FH (IIa). Eruptive xanthoma + abdominal pain → hyperTG (I/V).
• Secondary dyslipidaemia: hypothyroidism (↑ LDL), nephrotic syndrome (↑ LDL/VLDL), diabetes & alcohol (↑ TAG), cholestasis (↑ Lp-X). Always exclude secondary causes before labelling primary.
• Type III vs IIb: both raise cholesterol + TAG, but type III shows apo E2/E2, palmar xanthomas, broad-β band.

Recently asked / exam angle

• Rate-limiting enzymes: HMG-CoA reductase (synthesis), CYP7A1/7-α-hydroxylase (bile acids) — repeatedly asked one-liners.
• Apo C-II activates LPL; apo A-I activates LCAT; apo B-100 binds LDL receptor — direct single-best-answer favourites.
• LPL or apo C-II deficiency = Type I with pancreatitis and NO premature atherosclerosis — classic vignette.
• Tangier (ABCA1, orange tonsils), abetalipoproteinaemia (MTP, acanthocytes, vit E), and apo E2 = type III, palmar xanthoma — image/clue-based MCQs.
• Statins → ↑ LDL receptors (mechanism question); PCSK9 degrades LDL receptor; bempedoic acid → ATP-citrate lyase.
• Friedewald formula and its invalidity above TAG 400 — applied numerical item.
• NPC1L1 = ezetimibe target; PPAR-α = fibrate target — receptor/target matching.
• Squalene monooxygenase / lanosterol as cholesterol precursors; active isoprene = isopentenyl-PP.

Rapid revision

1. HMG-CoA reductase = rate-limiting enzyme of cholesterol synthesis; needs 2 NADPH; statin target.
2. Cholesterol is excreted only as bile acids/free cholesterol — humans cannot oxidise its ring.
3. CYP7A1 (7-α-hydroxylase) = rate-limiting step of bile acid synthesis; bile acids inhibit it.
4. Primary bile acids = cholic + chenodeoxycholic; secondary = deoxycholic + lithocholic.
5. Density HDL > LDL > IDL > VLDL > chylomicron; size is the reverse order.
6. Apo B-48 = chylomicrons; apo B-100 = VLDL/IDL/LDL + LDL-receptor ligand.
7. Apo C-II activates LPL; apo C-III inhibits it; apo A-I activates LCAT; apo E = remnant uptake.
8. Type I = LPL/apo C-II deficiency → ↑↑ chylomicrons, pancreatitis, no atherosclerosis.
9. Familial hypercholesterolaemia (IIa) = LDL-receptor defect, AD, tendon xanthomas, premature CAD.
10. Type III = apo E2/E2, IDL accumulation, palmar (tuberoeruptive) xanthomas, broad-β band.
11. Tangier = ABCA1 defect, orange tonsils, very low HDL; abetalipoproteinaemia = MTP defect, acanthocytes.
12. Statin = DOC for high LDL; fibrate (PPAR-α) = DOC for high TAG; PCSK9 inhibitors for homozygous FH.