T10 - Bile Acid Biosynthesis

Question 1

What are the two pathways of bile acid synthesis? Which is more commonly used?

Answer 1

classic pathway (more commonly used, 75% of the time)

alternate pathway (used 25% of the time)

Question 2

What does the term “enterohepatic circulation” refer to?

Answer 2

continuous movement of bile acids between liver and gut

Question 3

Write out a highly generalized pathway of bile acid movement.

Answer 3

liver → gall bladder → duodenum → [peristalsis] → jejunum → ileum [site of reabsorption] → sent back to liver

Question 4

Describe the solubility of bile acids in water.

Answer 4

highly water soluble

Question 5

Describe the function of bile acids as detergents. (2)

Answer 5

solubilize vitamins ADEK [fat-soluble]

solubilize bilirubin

Question 6

What is bilirubin?

Answer 6

breakdown products of heme extracted from hemoglobin

Question 7

Where does bile acid-mediated solubilization of vitamins A/D/E/K occur?

Answer 7

small intestine

Question 8

Where does bile acid-mediated solubilization of bilirubin occur?

Answer 8

liver

Question 9

What is the function of bile acid binding resins?

Answer 9

increase synthesis of bile acids

Question 10

Describe the pathway of the bile acid binding resin mechanism. (3)

Answer 10

induce synthesis of LDLR → more uptake of cholesterol → more cholesterol available for bile acid synthesis

Question 11

How many carbons do cholesterol and a bile acid have?

Answer 11

cholesterol = 27 carbons

bile acid = 24 carbons

Question 12

Describe what generally occurs when cholesterol is converted to a bile acid. (2)

Answer 12

3 C atoms removed from cholesterol side chain

hydroxylation to facilitate water-solubility

Question 13

Write out the classic pathway of bile acid synthesis.

Answer 13

cholesterol → [cholesterol 7α-hydroxylase] → 7α-hydroxy-cholesterol →→→ 7α-hydroxyl bile acids

Question 14

Write out the alternate pathway of bile acid synthesis.

Answer 14

cholesterol → oxysterols → [oxysterol 7α-hydroxylase] → 7α-hydroxy oxysterols →→→ 7α-hydroxyl bile acids

Question 15

What is the committed step in the conversion of cholesterol to bile acids?

Answer 15

addition of 7α-hydroxyl group

Question 16

What is the rate-limiting step of bile acid synthesis?

Answer 16

conversion of cholesterol → bile acid, catalyzed by cholesterol 7α-hydroxylase

Question 17

Differentiate between the classic and alternate pathways of bile acid synthesis in terms of activity.

Answer 17

classic = highly regulated

alternate = constitutively active (always on) → prevents build-up of toxic oxysterols in liver

Question 18

At what point do the classic and alternate pathways of bile acid synthesis converge? What is the significance of this point?

Answer 18

converge on the enzyme 3β-hydroxy-Δ⁵-C₂₇ steroid oxidoreductase

after this point, all enzymes are shared by the two pathways

Question 19

The synthesis of bile acids is tightly regulated at what level?

Answer 19

transcriptional level

Question 20

(T/F) Several enzymes in the classic pathway of bile acid synthesis are targets of transcriptional regulation.

Answer 20

False. Only the enzyme cholesterol 7α-hydroxylase is a target of transcriptional regulation.

Question 21

Write out the pathway of events that occur when bile acids accumulate.

Answer 21

bile acid accumulation → activate FXR transcription factor → turns on SHP gene → SHP protein binds to LRH nuclear receptor and turns it off → LHR required for cholesterol 7α-hydroxylase activity → bile acid synthesis inhibited

Question 22

Describe the significance of the LXR protein in the context of regulation of bile acid synthesis.

Answer 22

only present in rodents:

oxysterol accumulation → activates LXR → LXR + LRH activate cholesterol 7α-hydroxylase → increased bile acid synthesis → protection against cholesterol accumulation

Question 23

Jaundice is caused by

Answer 23

accumulation of bilirubins in tissues and blood

Question 24

What causes rickets (failure to mineralize bone)?

Answer 24

failure to solubilize vitamin D → impaired calcium metabolism + bone defects

Question 25

What causes recurrent bleeding episodes in patients with bile acid synthesis defects?

Answer 25

vitamin K deficiency → no carboxylation of blood clotting factors

Question 26

What causes steatorrhea (fatty yellow stools) in patients with defects in bile acid synthesis? (2)

Answer 26

bile acids not present to solubilize/cleave dietary TGs

no bilirubin (bilirubin gives stool brown color)

Question 27

What is seen in a liver biopsy of a patient with defects in bile acid synthesis? (3)

Answer 27

giant cell formation (fusion of adjacent hepatocytes)

micronodular cirrhosis

portal fibrosis

Question 28

When subcellular fractionation is performed on a biopsy of a patient with defects in bile acid synthesis, a greenish hue is seen. Why?

Answer 28

accumulation of biliverdin (bilirubin breakdown product) in tissue

Question 29

What happens if there are defects in 3β-hydroxy-Δ⁵-C₂₇ steroid oxidoreductase, the enzyme at the convergence point of the classic and alternate pathways? (2)

Answer 29

preceding two sterol intermediates accumulate, causing liver damage and pruritis

Question 30

What is the basis of the mutation that results in defective 3β-hydroxy-Δ⁵-C₂₇ steroid oxidoreductase?

Answer 30

point mutation that results in premature stop codon

Question 31

What is the mechanism behind oral bile acid therapy? (8)

Answer 31

bile acids consumed → solubilize nutrients → uptaken in ileum → return to liver → activation of FXR → SHP → blocks LRH → inhibits endogenous bile acid synthesis (and therefore avoids toxic intermediate accumulation)

Question 32

What is the Prometheus effect?

Answer 32

liver will regenerate following oral bile acid therapy assuming disease has not progressed too far

Question 33

Defects in sterol 27-hydroxylase, a bile acid synthesis enzyme that catalyzes reactions at two different points, results in

Answer 33

impairment of the enzyme → liver failure → progressive neuropathy called cerebrotendinous xanthomatosis (CTX)

Question 34

Is oral bile acid therapy effective for defects in the alternate pathway?

Answer 34

No. You would need to give a liver transplant instead.

Question 35

What are the most common bile acid synthesis deficiencies?

Answer 35

mutations to sterol 27-hydroxylase

mutations to 3β-hydroxy-Δ⁵-C₂₇ steroid oxidoreductase

Question 36

How do gallstones develop?

Answer 36

hypersecretion of cholesterol or hyposecretion of bile acids into bile ducts

Question 37

What are the treatment options for gallstones?

Answer 37

cholecystectomy

ursodiol, which dissovles the gallstones via regulation of bile acid synthesis

Question 38

How does ursodiol work?

Answer 38

bile acid analog that doesn’t bind to FXR but nonetheless increases circulating bile acid pool size, which re-establishes equilibrium such that cholesterol in bile is solubilized in micelles

Question 39

What is the downside to ursodiol treatment?

Answer 39

takes a long time to work

Question 40

What increases the effectiveness of ezetimibe?

Answer 40

administration along with statins

Question 41

Give an example of a bile acid binding resin.

Answer 41

cholestyramine

Question 42

Cholestyramine is useful to administer to what kind of patient?

Answer 42

women planning to get pregnant, because it does not have major systemic side effects

Question 43

Cholestyramine should NOT be administered to what kind of patient?

Answer 43

patients with pre-existing GI problems

Question 44

What is the major side effect of statins?

Answer 44

myopathy

Question 45

What is a common side effect of ezetimibe?

Answer 45

constipation