Overview
Cholesterol is a 27-carbon amphipathic sterol that is simultaneously indispensable and dangerous. It is the primary modulator of membrane fluidity in mammalian cells, the obligate precursor to all five classes of steroid hormones, bile acids, and vitamin D, and the dominant lipid component of myelin sheaths. Yet its accumulation in arterial walls drives the leading cause of death worldwide — atherosclerotic cardiovascular disease.
The body acquires cholesterol through two routes: de novo synthesis (primarily in the liver, ~700–900 mg/day) via the mevalonate pathway, and dietary absorption (~200–500 mg/day) in the small intestine. Hepatic HMGCR (HMG-CoA reductase) catalyzes the committed, rate-limiting step (HMG-CoA → mevalonate). Plasma cholesterol is transported in lipoprotein particles — VLDL, IDL, LDL, HDL — each with distinct apolipoproteins, receptors, and metabolic fates.
Cellular cholesterol homeostasis depends on the SREBP-2 / SCAP / INSIG feedback circuit: when ER cholesterol is low, SCAP escorts SREBP-2 to the Golgi for proteolytic activation; the released transcription factor upregulates both HMGCR and the LDL receptor (LDLR). Statins exploit this circuit. PCSK9 serine protease degrades LDLR in lysosomes, and anti-PCSK9 antibodies are now first-line therapy for familial hypercholesterolaemia.
Structure
Cholesterol is a tetracyclic compound (three cyclohexane rings A–C fused to a cyclopentane ring D), with a 3β-hydroxyl group (hydrophilic head), an isooctyl side chain at C17, and a double bond at C5–C6. In biological membranes the OH faces the aqueous phase while the rigid sterol nucleus intercalates between phospholipid acyl chains.
| Feature | Detail |
|---|---|
| Ring system | Fused A-B-C-D tetracycle (perhydrophenanthrene + cyclopentane) |
| Polar head | 3β-OH (hydrogen-bond donor; faces aqueous phase) |
| Rigid body | Planar ring nucleus reduces membrane disorder in fluid phase |
| Side chain | 8-carbon isooctyl at C17; contributes hydrophobic tail |
| Double bond | Δ5 (C5-C6) — absent in cholestanol, affects membrane properties |
| Membrane orientation | 3β-OH anchors at glycerophospholipid glycerol; nucleus alongside acyl chains |
| Lipid rafts | Cholesterol + sphingomyelin form ordered liquid phase (Lo) microdomains |
In the plasma, cholesterol is primarily esterified (cholesteryl ester, CE) at the C3 hydroxyl by LCAT (lecithin-cholesterol acyltransferase) — CE is more hydrophobic and resides in the lipoprotein core. Free cholesterol (FC) sits at the surface monolayer and in membranes.
Mechanism — Mevalonate Pathway & LDLR Circuit
De novo synthesis proceeds from acetyl-CoA through a cascade of ~30 reactions. HMGCR (the statin target) is the committed step. Downstream, squalene cyclises to lanosterol, which is further demethylated and reduced to cholesterol. PCSK9 counters LDLR-mediated clearance. Reverse cholesterol transport by HDL removes excess cholesterol from peripheral tissues.
┌────────────────────────────────────────────────────────────────────────┐
│ DE NOVO SYNTHESIS (liver / all nucleated cells) │
│ │
│ Acetyl-CoA ──► Acetoacetyl-CoA ──► HMG-CoA │
│ │ │
│ HMGCR (rate-limiting) │
│ ◄──── STATINS inhibit │
│ │ │
│ Mevalonate │
│ │ │
│ ┌────────────┴────────────┐ │
│ Isoprenoids Dolichol │
│ (farnesyl, geranyl) CoQ10, heme │
│ │ │
│ Squalene │
│ │ (squalene synthase) │
│ Lanosterol │
│ │ (19 demethylation steps) │
│ Cholesterol ◄───────────────── │
└─────────────────────────┬──────────────────────────┘ │
│ │
┌─────────────────────────▼──────────────────────────┐ │
│ LDLR PATHWAY (hepatocyte) │ │
│ │ │
│ Plasma LDL │ │
│ (apoB100) ──► LDLR on hepatocyte surface ─► Clathrin endocytosis │
│ │ │
│ ┌── PCSK9 (serine protease) │ │
│ │ secreted; binds LDLR EGF-A │ │
│ │ → lysosomal LDLR degradation │ │
│ │ ◄─── Anti-PCSK9 mAb block │ │
│ │ (evolocumab, alirocumab) │ │
│ │ │ │
│ LDLR recycled ◄┘ LDL internalized │ │
│ (low cholesterol state) → lysosomal CE hydrolysis │
│ → free cholesterol │
│ │ │
│ ┌───────── FEEDBACK LOOP ────────┴──────────────────┐ │
│ │ ER cholesterol HIGH → SCAP/INSIG retain SREBP-2 │ │
│ │ ER cholesterol LOW → SCAP escorts SREBP-2 │ │
│ │ to Golgi → S1P/S2P cleavage │
│ │ → SREBP-2 nuclear entry │ │
│ │ → ↑ HMGCR + ↑ LDLR genes │ │
│ └──────────────────────────────────────────────────-┘ │
│ │
│ REVERSE CHOLESTEROL TRANSPORT │
│ │
│ Peripheral cells → ABCA1/ABCG1 → nascent HDL │
│ │ (apoA-I scaffold) │
│ LCAT (lecithin:cholesterol acyltransferase) │
│ │ → cholesteryl ester core │
│ Mature HDL │
│ │ │
│ ┌──────┴──────────┐ │
│ SR-B1 (liver) CETP → LDL/VLDL │
│ cholesterol uptake (CE transfer) │
└────────────────────────────────────────────────────────────────────-┘- Acetyl-CoA condenses to HMG-CoA (3 enzymes); HMGCR reduces HMG-CoA to mevalonate — rate-limiting step, feedback-regulated by SREBP-2 and sterol-accelerated HMGCR degradation.
- Mevalonate → farnesyl-PP → squalene (squalene synthase) → lanosterol (oxidosqualene cyclase) → cholesterol (19 demethylation/reduction steps, 450 nm CYP51A1 demethylase).
- LDL binds LDLR via apoB100; clathrin-coated pit endocytosis; endosome acidification releases LDL → lysosomal NPC1/NPC2 exports free cholesterol to ER.
- PCSK9 binds LDLR EGF-A domain at the cell surface; co-internalized; low endosomal pH causes tight PCSK9–LDLR interaction → LDLR degraded, not recycled.
- ABCA1 (ATP-binding cassette A1) exports free cholesterol and phospholipids to lipid-poor apoA-I → pre-β HDL → LCAT esterifies cholesterol → spherical HDL3 → HDL2 → SR-B1 delivers CE to liver (selective uptake).
- CETP (cholesteryl ester transfer protein) exchanges CE from HDL to VLDL/LDL and triglycerides in reverse — a pharmaceutical target (anacetrapib, obicetrapib).
Physiological Roles
| Role | Detail |
|---|---|
| Membrane fluidity buffer | At body temperature, cholesterol fills gaps between unsaturated acyl chains, reducing permeability while preventing gel phase; increases membrane thickness |
| Lipid raft formation | Liquid-ordered (Lo) phase microdomains with sphingomyelin concentrate GPI-anchored proteins, RTKs, and signaling molecules; key for T-cell receptor clustering |
| Steroid hormone precursor | Mitochondrial CYP11A1 cleaves side chain to pregnenolone → glucocorticoids, mineralocorticoids, androgens, estrogens, progestogens |
| Bile acid synthesis | CYP7A1 (rate-limiting) converts cholesterol to 7α-hydroxycholesterol → primary bile acids (cholic, chenodeoxycholic) → bile salt detergent for fat absorption |
| Vitamin D synthesis | 7-dehydrocholesterol (skin) → UV-B → previtamin D3 → cholecalciferol → 25-OH-D3 (liver) → 1,25-(OH)₂D3 (kidney) |
| Myelin sheath insulation | Oligodendrocytes/Schwann cells are 70–80% lipid by dry weight; cholesterol is the dominant sterol; critical for saltatory conduction |
| Hedgehog signalling | Sonic Hedgehog (SHH) undergoes autocatalytic cholesterol modification at C-terminal Cys; cholesterol-modified SHH is essential for tissue patterning |
Pharmacology & Clinical Use
Statins (HMG-CoA reductase inhibitors) — rosuvastatin, atorvastatin, simvastatin. Competitively inhibit HMGCR at the active site; cause hepatic ER cholesterol depletion → SREBP-2 activation → ↑LDLR expression → ↑ LDL-C clearance (net 30–60% LDL-C reduction). Also pleiotropic effects: anti-inflammatory, endothelial NO↑, plaque stabilization. Class-effect side effects: myopathy (CK elevation), rare rhabdomyolysis (CYP3A4 DDIs), new-onset T2DM (2–10% risk elevation).
PCSK9 inhibitors — evolocumab (Repatha) and alirocumab (Praluent) are monoclonal antibodies blocking PCSK9 before it binds LDLR. Additional 50–70% LDL-C lowering on top of statins; approved for FH and high-risk ASCVD. Inclisiran is a siRNA targeting hepatic PCSK9 mRNA with twice-yearly dosing.
Ezetimibe — inhibits NPC1L1 transporter in the small intestinal brush border; blocks cholesterol absorption (~18% LDL-C reduction alone; additive with statins — IMPROVE-IT trial).
Bile acid sequestrants — cholestyramine, colesevelam. Bind bile acids in the intestine → bile acid recycling interrupted → liver upregulates CYP7A1 → more cholesterol converted to bile acids → LDLR upregulation. Limited use due to GI side effects; safe in pregnancy.
Fibrates (PPARα agonists) — primarily lower triglycerides 20–50% and modestly raise HDL-C; used in hypertriglyceridaemia and mixed dyslipidaemia. Bezafibrate, fenofibrate.
Pathology
| Condition | Mechanism | Key Feature |
|---|---|---|
| Familial hypercholesterolaemia (FH) | Loss-of-function LDLR or PCSK9 gain-of-function; LDL-C 2–4× normal | Tendon xanthomas, corneal arcus, premature ASCVD; heterozygous FH ~1/250 |
| Atherosclerosis | LDL retained in arterial intima → oxidised LDL → macrophage foam cells → lipid core → fibrous cap → plaque rupture → MI/stroke | LDL-C is causal (Mendelian randomisation); each 1 mmol/L LDL-C = ~20% relative CVD risk |
| Smith-Lemli-Opitz syndrome | DHCR7 (7-dehydrocholesterol reductase) deficiency; cholesterol synthesis block → 7-DHC accumulation | Intellectual disability, syndactyly 2-3 toes, genital abnormalities; treat with dietary cholesterol |
| Tangier disease | ABCA1 loss-of-function; cholesterol efflux to HDL absent; HDL-C near zero; cholesterol accumulates in macrophages | Orange tonsils, peripheral neuropathy, hepatosplenomegaly, premature ASCVD |
| Niemann-Pick type C | NPC1/NPC2 dysfunction; cholesterol trapped in late endolysosomes despite normal cholesterol synthesis | Vertical supranuclear gaze palsy, ataxia, dementia; treatment: miglustat, arimoclomol |
| Gallstones (cholesterol) | Bile supersaturation with cholesterol (↑biliary cholesterol secretion via ABCG5/8 or ↓bile acids); cholesterol nucleates in gallbladder | Most common type in Western countries; risk: female, fat, fertile, forty, fibre-poor diet |
| Sitosterolaemia | ABCG5/ABCG8 mutations → dietary plant sterols absorbed and not excreted; mimics FH | Xanthomas, haemolytic anaemia, premature ASCVD; treat with ezetimibe |
Connections
Cholesterol metabolism is linked to glucose metabolism (insulin activates HMGCR via PP2A; diabetes raises PCSK9), thyroid hormones (hypothyroidism raises LDL-C via ↓LDLR expression), and obesity/leptin. Mevalonate pathway intermediates (geranylgeranyl-PP) are required for Rac/Rho GTPase prenylation — statin effects on immune cells partly reflect this. Bile acid receptor (FXR) signalling crosstalk influences hepatic glucose and lipid metabolism.
References
- Goldstein JL & Brown MS (2015). A century of cholesterol and coronaries. Cell 161:161–172.
- Horton JD, Goldstein JL, Brown MS (2002). SREBPs: activators of the complete program of cholesterol and fatty acid synthesis. J Clin Invest 109:1125–1131.
- Abifadel M et al. (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolaemia. Nature Genetics 34:154–156.
- Cholesterol Treatment Trialists' (CTT) Collaboration (2010). Efficacy and safety of more intensive lowering of LDL cholesterol. Lancet 376:1670–1681.
- Sabatine MS et al. (2017). Evolocumab and clinical outcomes in patients with cardiovascular disease (FOURIER). NEJM 376:1713–1722.
- Ference BA et al. (2017). Low-density lipoproteins cause atherosclerotic cardiovascular disease. Eur Heart J 38:2459–2472.
- Tall AR, Yvan-Charvet L (2015). Cholesterol, inflammation and innate immunity. Nat Rev Immunol 15:104–116.