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Biochemistry · Metabolic pathway

Classic bile acid synthesis pathway !

The liver turns cholesterol into bile acids, which help digest fat. It is also the main way the body gets rid of cholesterol.

Updated 2026-11-01

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Key facts

  • Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting step; bile acids returning from the gut repress it (FXR–SHP and FGF19).
  • The primary bile acids are cholic acid (needs 12α-hydroxylation by CYP8B1) and chenodeoxycholic acid (made without it).
  • Conjugation with glycine or taurine (BAAT) lowers the pKa, so bile salts stay ionised and soluble in the intestine.
  • About 95% of bile acids are reabsorbed in the terminal ileum and return to the liver (enterohepatic circulation).
  • Gut bacteria deconjugate and 7α-dehydroxylate them to the secondary bile acids, deoxycholic and lithocholic acid.

Regulation

  • Bile acids activate FXR in hepatocytes (SHP) and in the ileum (FGF19), and both signals repress CYP7A1.
  • Insulin, the fed state and a daily rhythm change CYP7A1 activity.
  • Bile acid sequestrants interrupt the return to the liver, so CYP7A1 rises and the liver uses more cholesterol, lowering LDL.

The steps, one by one

  1. Step 1 · Cholesterol 7α-hydroxylase (CYP7A1) irreversible Cholesterol + NADPH + o2 → 7α-Hydroxycholesterol + nadp + H₂OIn the endoplasmic reticulum it adds a 7α-hydroxyl to cholesterol: the committed and slowest step.If it fails: CYP7A1 deficiency (rare): high LDL cholesterol and early gallstones that respond poorly to statins. Gallstones (cholelithiasis) →
  2. Step 2 · 3β-Hydroxy-Δ5-C27-steroid dehydrogenase (HSD3B7) irreversible 7α-Hydroxycholesterol + NAD⁺ → 7α-Hydroxy-4-cholesten-3-one (C4) + NADHOxidises the 3-hydroxyl and shifts the double bond to ring A, giving C4, whose blood level mirrors how fast bile acids are being made.If it fails: HSD3B7 deficiency: neonatal cholestasis and poor absorption of fat-soluble vitamins; it responds to oral primary bile acids.
  3. Step 3 · Sterol 12α-hydroxylase (CYP8B1) irreversible 7α-Hydroxy-4-cholesten-3-one (C4) + NADPH + o2 → 7α,12α-Dihydroxy-4-cholesten-3-one + nadp + H₂OAdds the 12α-hydroxyl that defines cholic acid; intermediates that skip this step become chenodeoxycholic acid.If it fails: Its activity sets the ratio of cholic to chenodeoxycholic acid; no classic human deficiency disease is described.
  4. Step 4 · Δ4-3-Oxosteroid 5β-reductase (AKR1D1), then 3α-hydroxysteroid dehydrogenase (AKR1C4) irreversible 7α,12α-Dihydroxy-4-cholesten-3-one + NADPH → 5β-Cholestane-3α,7α,12α-triol + nadpSaturates ring A in the 5β orientation and reduces the 3-oxo group to a 3α-hydroxyl, giving the bent shape typical of bile acids.If it fails: AKR1D1 deficiency: neonatal cholestasis with abnormal Δ4-3-oxo bile acids; it responds to primary bile acids.
  5. Step 5 · Sterol 27-hydroxylase (CYP27A1) and peroxisomal side-chain shortening irreversible 5β-Cholestane-3α,7α,12α-triol + NADPH + o2 → Choloyl-CoA + Propionyl-CoAMitochondrial CYP27A1 oxidises the end of the side chain to a carboxylic acid, and in the peroxisome one round of β-oxidation removes three carbons as propionyl-CoA, leaving choloyl-CoA.If it fails: CYP27A1 deficiency causes cerebrotendinous xanthomatosis; peroxisomal disorders such as Zellweger syndrome leave C27 bile acid intermediates. Zellweger syndrome (Zellweger spectrum) →
  6. Step 6 · Bile acid-CoA:amino acid N-acyltransferase (BAAT) irreversible Choloyl-CoA + Glycine (or taurine) → Glycocholic acid (taurocholic acid with taurine) + coenzyme AJoins glycine or taurine to choloyl-CoA, making the bile salts that are secreted into bile.If it fails: BAAT deficiency leaves bile acids unconjugated: fat and fat-soluble vitamin malabsorption with itching.

Clinical notes

  • Gallstones form when bile carries too much cholesterol for its bile salts and phospholipids.
  • Loss of the terminal ileum (resection or Crohn disease) wastes bile acids: bile acid diarrhoea and fat malabsorption.
  • Cerebrotendinous xanthomatosis (CYP27A1): tendon xanthomas, cataracts, chronic diarrhoea and neurological decline; it is treated with chenodeoxycholic acid.
  • Peroxisomal disorders such as Zellweger syndrome block side-chain shortening, and C27 bile acid intermediates accumulate.

Pathways

Test yourself

Think of the answer, then tap the question to see it.

Which enzyme limits the rate of bile acid synthesis, and what represses it?

CYP7A1 (cholesterol 7α-hydroxylase); bile acids returning from the gut repress it through FXR, SHP and FGF19.

What does conjugation with glycine or taurine achieve?

It lowers the pKa, so bile salts stay ionised, soluble and inside the intestinal lumen, where they emulsify fat.

How do bile acid sequestrants lower LDL?

They block reabsorption; CYP7A1 is freed from feedback, the liver uses cholesterol to make bile acids and raises its LDL receptors.

Which bile acids are secondary, and who makes them?

Deoxycholic and lithocholic acid, made by colonic bacteria from cholic and chenodeoxycholic acid.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: Cerebrotendinous xanthomatosis: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); HSD3B7 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); AKR1D1 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Bile acid-CoA:amino acid N-acyltransferase (BAAT) - Homo sapiens (UniProt, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Representative model, for educational purposes only.