What is the acid synthesized in the liver, stored in the gallbladder (GB), and secreted from the bile duct?

Bile Acid Synthesis, Storage, and Secretion

Bile acids are synthesized in the liver from cholesterol, stored in the gallbladder, and secreted through the bile duct into the duodenum. 1

Bile Acid Synthesis

Bile acid synthesis occurs through two main pathways:

1. Classical (Neutral) Pathway:

   • Primary pathway for bile acid synthesis
   • Occurs in the liver hepatocytes
   • Produces both cholic acid (CA) and chenodeoxycholic acid

2. Acidic (Alternative) Pathway:

   • Secondary pathway for bile acid synthesis
   • Involves mitochondrial sterol 27-hydroxylase (CYP27A1)
   • Key regulatory steps include:
     • Cholesterol transport by steroidogenic acute regulatory protein (StarD1)
     • 7α-hydroxylation of oxysterols by oxysterol 7α-hydroxylase (CYP7B1) 2

Biochemical Process

• Bile acids are synthesized from cholesterol through multiple enzymatic conversions
• At least 17 different enzymes are required for the complete synthesis process 3
• The primary bile acids produced are:
  • Cholic acid (CA)
  • Chenodeoxycholic acid 1
• After synthesis, bile acids are conjugated with either:
  • Glycine
  • Taurine 4
• Conjugation makes bile acids more water-soluble and impermeable to cell membranes 5

Storage and Secretion

1. After synthesis and conjugation in the liver:

   • Bile acids enter the portal vein
   • Undergo efficient first-pass extraction by the liver
   • Are secreted into hepatic bile ducts 4

2. Storage:

   • Bile acids in bile are concentrated in the gallbladder during fasting 6
   • The gallbladder serves as the primary storage reservoir

3. Secretion:

   • In response to dietary fat, the gallbladder contracts
   • Bile acids are expelled into the duodenum via the cystic and common bile ducts 4
   • This process is triggered by physiologic responses to eating

Enterohepatic Circulation

• About 90% of a therapeutic dose of bile acids is absorbed in the small bowel 4
• After intestinal absorption, bile acids return to the liver via the portal vein
• Only small quantities appear in systemic circulation
• Very small amounts are excreted in urine 4
• The enterohepatic circulation is highly efficient, with each bile acid molecule undergoing multiple cycles before excretion 5

Clinical Significance

• Bile acids are essential for:

  • Digestion and absorption of lipids in the gut
  • Maintenance of cholesterol homeostasis
  • Induction of bile flow
  • Excretion of toxic substances
  • Regulation of energy metabolism through signaling pathways 3, 6

• Disorders of bile acid synthesis can present with:

  • Cholestatic liver disease
  • Neuropsychiatric symptoms
  • Spastic paraplegias 3

• Genetic defects in bile acid synthesis are rare but treatable:

  • The most frequent defects are 3β-HSD deficiency (due to variants in HSD3B7) and D4-3-oxoR deficiency (due to variants in AKR1D1) 1
  • Treatment with oral primary bile acids is strongly recommended for these conditions 1

Bile Acid Metabolism Disorders

Defects in bile acid synthesis can result from:

• Genetic mutations affecting the synthesis pathway
• Defective conjugation
• Defective membrane transport
• Increased bacterial degradation during enterohepatic cycling 5

These disorders may require treatment with bile acid replacement therapy or ursodeoxycholic acid (UDCA) to improve liver function and prevent disease progression 5.