T10 - Bile Acid Biosynthesis Flashcards
What are the two pathways of bile acid synthesis? Which is more commonly used?
classic pathway (more commonly used, 75% of the time)
alternate pathway (used 25% of the time)
What does the term “enterohepatic circulation” refer to?
continuous movement of bile acids between liver and gut
Write out a highly generalized pathway of bile acid movement.
liver → gall bladder → duodenum → [peristalsis] → jejunum → ileum [site of reabsorption] → sent back to liver
Describe the solubility of bile acids in water.
highly water soluble
Describe the function of bile acids as detergents. (2)
solubilize vitamins ADEK [fat-soluble]
solubilize bilirubin
What is bilirubin?
breakdown products of heme extracted from hemoglobin
Where does bile acid-mediated solubilization of vitamins A/D/E/K occur?
small intestine
Where does bile acid-mediated solubilization of bilirubin occur?
liver
What is the function of bile acid binding resins?
increase synthesis of bile acids
Describe the pathway of the bile acid binding resin mechanism. (3)
induce synthesis of LDLR → more uptake of cholesterol → more cholesterol available for bile acid synthesis
How many carbons do cholesterol and a bile acid have?
cholesterol = 27 carbons
bile acid = 24 carbons
Describe what generally occurs when cholesterol is converted to a bile acid. (2)
3 C atoms removed from cholesterol side chain
hydroxylation to facilitate water-solubility
Write out the classic pathway of bile acid synthesis.
cholesterol → [cholesterol 7α-hydroxylase] → 7α-hydroxy-cholesterol →→→ 7α-hydroxyl bile acids
Write out the alternate pathway of bile acid synthesis.
cholesterol → oxysterols → [oxysterol 7α-hydroxylase] → 7α-hydroxy oxysterols →→→ 7α-hydroxyl bile acids
What is the committed step in the conversion of cholesterol to bile acids?
addition of 7α-hydroxyl group
What is the rate-limiting step of bile acid synthesis?
conversion of cholesterol → bile acid, catalyzed by cholesterol 7α-hydroxylase
Differentiate between the classic and alternate pathways of bile acid synthesis in terms of activity.
classic = highly regulated
alternate = constitutively active (always on) → prevents build-up of toxic oxysterols in liver
At what point do the classic and alternate pathways of bile acid synthesis converge? What is the significance of this point?
converge on the enzyme 3β-hydroxy-Δ5-C27 steroid oxidoreductase
after this point, all enzymes are shared by the two pathways
The synthesis of bile acids is tightly regulated at what level?
transcriptional level
(T/F) Several enzymes in the classic pathway of bile acid synthesis are targets of transcriptional regulation.
False. Only the enzyme cholesterol 7α-hydroxylase is a target of transcriptional regulation.
Write out the pathway of events that occur when bile acids accumulate.
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
Describe the significance of the LXR protein in the context of regulation of bile acid synthesis.
only present in rodents:
oxysterol accumulation → activates LXR → LXR + LRH activate cholesterol 7α-hydroxylase → increased bile acid synthesis → protection against cholesterol accumulation
Jaundice is caused by
accumulation of bilirubins in tissues and blood
What causes rickets (failure to mineralize bone)?
failure to solubilize vitamin D → impaired calcium metabolism + bone defects
What causes recurrent bleeding episodes in patients with bile acid synthesis defects?
vitamin K deficiency → no carboxylation of blood clotting factors
What causes steatorrhea (fatty yellow stools) in patients with defects in bile acid synthesis? (2)
bile acids not present to solubilize/cleave dietary TGs
no bilirubin (bilirubin gives stool brown color)
What is seen in a liver biopsy of a patient with defects in bile acid synthesis? (3)
giant cell formation (fusion of adjacent hepatocytes)
micronodular cirrhosis
portal fibrosis
When subcellular fractionation is performed on a biopsy of a patient with defects in bile acid synthesis, a greenish hue is seen. Why?
accumulation of biliverdin (bilirubin breakdown product) in tissue
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)
preceding two sterol intermediates accumulate, causing liver damage and pruritis
What is the basis of the mutation that results in defective 3β-hydroxy-Δ5-C27 steroid oxidoreductase?
point mutation that results in premature stop codon
What is the mechanism behind oral bile acid therapy? (8)
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)
What is the Prometheus effect?
liver will regenerate following oral bile acid therapy assuming disease has not progressed too far
Defects in sterol 27-hydroxylase, a bile acid synthesis enzyme that catalyzes reactions at two different points, results in
impairment of the enzyme → liver failure → progressive neuropathy called cerebrotendinous xanthomatosis (CTX)
Is oral bile acid therapy effective for defects in the alternate pathway?
No. You would need to give a liver transplant instead.
What are the most common bile acid synthesis deficiencies?
mutations to sterol 27-hydroxylase
mutations to 3β-hydroxy-Δ5-C27 steroid oxidoreductase
How do gallstones develop?
hypersecretion of cholesterol or hyposecretion of bile acids into bile ducts
What are the treatment options for gallstones?
cholecystectomy
ursodiol, which dissovles the gallstones via regulation of bile acid synthesis
How does ursodiol work?
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
What is the downside to ursodiol treatment?
takes a long time to work
What increases the effectiveness of ezetimibe?
administration along with statins
Give an example of a bile acid binding resin.
cholestyramine
Cholestyramine is useful to administer to what kind of patient?
women planning to get pregnant, because it does not have major systemic side effects
Cholestyramine should NOT be administered to what kind of patient?
patients with pre-existing GI problems
What is the major side effect of statins?
myopathy
What is a common side effect of ezetimibe?
constipation
