Last edited: 9/9/2021

BILE SYNTHESIS
Gastrointestinal | Bile Synthesis Medical Editor: Ilia-Preisyan Georgiev

OUTLINE II) BILE ACIDS

I) BILE CONTENTS (A) PRIMARY BILE ACIDS

II) BILE ACIDS
III) BILIRUBIN (1) Derived from cholesterol
IV) REVIEW QUESTIONS Cholesterol ways of production
V) REFRENCES o Delivered by chylomicrons from ingestion via the
exogenous pathway
o Synthesized from high levels of Acetyl CoA
o Recycled it through the lipoprotein pathway
Cholesterol molecule
o Four ring structures (A, B, C, D) AfraTafreeh.com
I) BILE CONTENTS
o Hydrocarbon side chain
(i) Bile acids o Double bond in the B-ring
o OH-group on the 3rd C-atom
 around 70%
 Responsible for the emulsification of fat (2) Cholesterol travels down

(ii) Bilirubin through the smooth endoplasmic reticulum

A portion of the hydrocarbon side chain is cleaved off and
(iii) Phospholipids an carboxylic group is added
 Derived from fatty acids There multiple enzymes affect it through hydroxylation
 Phosphatidylcholine - main one reactions
• Choline (essential, vitamin-like nutrient) reacts o 7-α-hydroxylase (CYP7E1)
with diacylglycerol to produce  Part of the cytochrome p450 system
phosphatidylcholine  Adds a OH-group on the 7th C-atom
 Makes the cholesterol soluble • Chenodeoxycholic acid comes out as a
 Helps emulsify some of the fat result
 Reduces the hepatotoxicity of the bile acids. o 12-α-hydroxylase (CYP8B1)
 Part of the cytochrome p450 system
(iv) Cholesterol AfraTafreeh.com  Affects cholesterol after CYP7E1
(v) Xenobiotics  Adds a OH-group on the 12th C-atom
 Substances that are: • Cholic acid comes out as a result
• not usually present in the human body (3) These are
• not usually produced in the human body
• in excessively high concentrations the two primary bile acids
o Slightly polar
(vi) Water o The liver can excrete them right in the biliary system
(vii) Electrolytes through specific transporters
 Bile salt export pump (BSEP)
 Sodium (Na+) o All primary and secondary bile acids have no double
 Calcium (Ca++) bond in the B-ring of cholesterol
 Bicarbonates (HCO3-)

(viii) Glutathione
 Antioxidant

(ix) IgA antibodies

 Inhibit bacterial growth

Figure 1 Synthesis of primary bile acids.

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 (B) BILE SALTS
(1) Primary bile acids
can also undergo conjugation
o Conjugation makes the molecules very polar
Each of them can go two different pathways
o Conjugation with the amino acid - Glycine
 Chenodeoxycholic acid →
Glycochenodeoxycholic acid
 Cholic acid → Glycocholic acid
o Conjugation with the amino acid - Taurine
 Chenodeoxycholic acid →
Taurochenodeoxycholic acid
 Cholic acid → Taurocholic acid
The substances produced are conjugated bile salts

Figure 2 Conjugation of primary bile acids.

(C) SECONDARY BILE ACIDS
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(1) The biliary system combines
with the pancreatic system
The common bile duct combines with the main pancreatic duct
o Form the ampulla of Vater (hepatopancretic ampulla)
 The opening of the ampulla is controlled by the sphincter of Oddi (hepatopancreatic sphincter)
(2) Through the ampulla
primary bile acids go to the duodenum
There they are metabolized by enzymes produced by the bacteria located in the intestine
o 7-α-dehidroxylase

Primary bile acids are converted into secondary bile acids Secondary bile acids can also conjugate with glycine and taurine
o Chenodeoxycholic acid → Litocholic acid o Litocholic acid → Glycolithocholic acid
o Cholic acid → Deoxycholic acid o Litocholic acid → Taurolithocholic acid
o Deoxycholic acid → Glycodeoxy acid
o Deoxycholic acid → Taurodeoxy acid
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Figure 3 Synthesis of secondary bile acids.

Figure 4 Conjugation of secondary bile acids
.
(D) ENTERO-HEPATIC CIRCULATION
(1) Bile acids are produced
in the liver
Secreted in the biliary system
Transported to the intestine
Metabolized by bacteria located there
o To secondary bile salts
The secondary bile acids are transported back to the liver
o via the portal circulation
(2) The hydroxylation by
7-α-hydroxylase (CYP7E1) is the rate limiting step
o slowest and one of the most important steps
o High levels of cholic acid and chenodeoxycholic acid
allosterically regulate (inhibit) that enzyme - Figure 1

Figure 5 Enterohepatic circulation.

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III) BILIRUBIN

(1) Bilirubin is the breakdown product of

the heme in hemoglobin
The breakdown of old and defective red blood cells
occurs in different organs with sinusoidal capillaries
o Spleen (main)
o Liver
o Red bone marrow
(2) The spleen has
macrophages in it
They engulf (phagocytose) old and defective red blood
cells
Inside hemoglobin gets broken down to heme and globin
o Globin is a protein
 Gets broken down to amino acids that are the
recycled
Heme gets broken down to Fe++ and biliverdin
o By the enzyme heme oxygenase
Figure 7 Bilirubin conjugation.
(3) Fe++ can be
(6) Conjugated bilirubin is
Remain in the macrophage
o Bind to apoferitin taken to the GIT
o Turn to ferritin Converted to urobilinogen
 Many ferritins make hemosiderin o By bacterial enzymes (proteases) in the GIT
Pushed out Some urobilinogen goes to the distal ileum
o Bound to a transport protein – transferrin o Gets reabsorbed
 Synthesized by the liver o Goes back to the liver
o Transferrin transports Fe++ around the body  Through the enterohepatic circulation
 The liver may use it to make more conjugated
(4) Biliverdin is bilirubin
reduced to bilirubin Some urobilinogen goes to the kidneys
o By the enzyme bilirubin reductase o Undergoes specific metabolism
Bilirubin is lipid soluble o Urobilin is produced
o Not very hydrophilic  Gives the yellow hue of the urine
Bilirubin needs to bind to a transport protein – albumin Some urobilinogen gets converted to stercobilin
o Synthesized by the liver o Gives the brown hue of the feces.
o Transports bilirubin via the blood circulation to the
liver

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Figure 6 Bilirubin production.
(5) The bilirubin that comes
in the liver is unconjugated bilirubin
o Doesn’t have a polar molecule attached to it
A glucuronic molecule (very polar) is transferred to it
o By the enzyme UDP-glucuronosyltransferase
(UGT)
o Conjugated bilirubin is produced
The conjugated bilirubin is exerted in the biliary system
o Through multi resistance associated peptide type
2 (MRP2)

Figure 8 Bilirubin products.

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IV) REVIEW QUESTIONS

What is the main component of the bile?
a. Bile acids
b. Bilirubin
c. Phospholipids
d. Cholesterol

Which is not considered a xenobiotic?

a. Substances not usually present in the human body
b. Substances not usually produced in the human body
c. Substances in excessively high concentrations
d. Substances produced in areas separated from the
general circulation

Which is not part of the cholesterol molecule?

a. Four ring structures (A, B, C, D)
b. Hydrocarbon side chain
c. Double bond in the C-ring
d. OH-group on the 3rd C-atom

In which organelle is cholesterol metabolized to bile

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acids?
a. Rough endoplasmic reticulum
b. Smooth endoplasmic reticulum
c. Ribosomes
d. Cytosol

Which substance is considered a primary bile acid?

a. Glycine
b. Chenodeoxycholic
c. Glycocholic
d. Litocholic

Which enzyme is produced by bacteria in the

intestine?
a. 7-α-hydroxylase
b. 12-α-hydroxylase
c. UDP-glucuronosyltransferase
d. 7-α-dehidroxylase

Which enzyme is considered rate limiting in the bile

acid synthesis?
a. 7-α-hydroxylase
b. 12-α-hydroxylase
c. UDP-glucuronosyltransferase
d. 7-α-dehidroxylase

Where is conjugated bilirubin produced

a. Spleen
b. Liver
c. Red bone marrow
d. Yellow bone marrow

Which protein binds Fe++?

a. Ferritin
b. Albumin
c. Apoferitin
d. Biliverdin

Which substance gives the yellow hue of the

urine?
a. Bilirubin
b. Urobilinogen
c. Urobilin
d. Stercobilin

V) REFRENCES

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