HEME → BILIRUBIN PATHWAY


  • Macrophage Role in Recycling RBCs
       - Old red blood cells (RBCs) are phagocytosed by macrophages located in the spleen, liver (Kupffer cells), and bone marrow.    - This process is essential for the breakdown and recycling of hemoglobin and its components.

  • Hemoglobin Breakdown Process
      1. Hemoglobin (the oxygen-carrying protein in red blood cells) is broken down into globin (the protein part) and heme (the iron-containing part).

  • Conversion of Heme to Bilirubin
      2. Heme is converted to biliverdin by Heme oxygenase.
         - Heme Oxygenase:
           - This enzyme breaks down heme using oxygen (O2) and NADPH as required agents.
           - The reaction produces Fe3+ (ferric ion) and CO (carbon monoxide), a significant byproduct.
           - Biliverdin is characterized by its green color, indicative of its structure.        - extHemeightarrowextbiliverdin(green)+extFe3++extCOext{Heme} ightarrow ext{biliverdin (green)} + ext{Fe}^{3+} + ext{CO}      3. Biliverdin is further reduced to unconjugated bilirubin by biliverdin reductase.
         - Unconjugated bilirubin is yellow in color due to its structure and is known for its inability to be excreted through urine directly.      

  • Transport of Unconjugated Bilirubin to the Liver
      4. Unconjugated bilirubin is transported in blood, bound to albumin, which helps in its solubility and transport to the liver.

  • Hepatic Uptake and Processing of Bilirubin
      5. Unconjugated bilirubin enters hepatocytes through the action of uptake transporters OATP1B1 and OATP1B3.
      6. Inside the hepatocyte, bilirubin binds to ligandin, a glutathione S-transferase (GST) protein, which helps in solubilizing it for upcoming reactions.
      7. Conjugation: Bilirubin is conjugated with glucuronic acid via UGT1A1 (UDP-glucuronosyltransferase), transforming it into conjugated bilirubin.
      8. The conjugated bilirubin is secreted into the bile canaliculus via the MRP2 (Multi-Drug Resistance Protein 2).

  • Storage and Concentration of Bile
      9. The bile canaliculus channels bile towards the bile duct, where it is further stored and concentrated in the gallbladder.

  • Gastrointestinal Release of Bile
      10. Upon eating, the hormone cholecystokinin (CCK) induces contraction of the gallbladder and relaxation of the Sphincter of Oddi, allowing bile to enter the small intestine, facilitating digestion.

B. CHOLESTEROL → BILE ACIDS PATHWAY

  • Bile Acid Synthesis
      - Cholesterol is converted into primary bile acids, specifically cholic acid and chenodeoxycholic acid, by the enzyme CYP7A1 (cholesterol 7 alpha-hydroxylase).
      - CYP7A1: This is the rate-limiting enzyme in bile acid synthesis from cholesterol.

C. ENTEROHEPATIC CIRCULATION (BILE SALTS)

  • Bile Salt Reabsorption
      1. Approximately 95% of bile salts are reabsorbed in the terminal ileum through the action of the sodium-dependent apical sodium-bile acid transporter (ASBT).   2. Bile salts exit enterocytes through the basolateral transporters OSTA and OSTβ into portal blood.
      3. The portal blood carries bile salts back to the liver where they can be reused.

  • Functions of Bile Salts in the Small Intestine:
      - Bile salts play a pivotal role in emulsifying fats and aiding the absorption of fat-soluble vitamins (A, D, E, and K).

D. FATE OF BILIRUBIN IN INTESTINE

  • Conjugated Bilirubin Degradation
      - Conjugated bilirubin enters the intestine and undergoes deconjugation and reduction by bacterial enzymes.
      - The result of this interaction is the formation of urobilinogen, a colorless degradation product, which further undergoes conversion in the large intestine.

KEY TRANSPORTERS / ENZYMES

  • Transporters and Their Functions:
      - OATP1B1/1B3: Hepatic uptake of unconjugated bilirubin (basolateral transport in hepatocytes).   - BSEP: Facilitates conjugated bilirubin secretion into bile (canalicular transport).
      - ASBT: An apical sodium-bile acid transporter located in the ileum.   - OSTA/OSTβ: Bile acid exit from enterocytes at the basolateral membrane.   - NTCP: Sodium-taurocholate co-transporting polypeptide responsible for liver uptake of bile salts.   - CYP7A1: The rate-limiting enzyme in bile acid synthesis from cholesterol.

REGULATION (FEEDBACK)

  • Feedback Mechanism of Bile Acid Synthesis:
      1. When bile acids reach the terminal ileum, they activate the farnesoid X receptor (FXR) in enterocytes.
      2. FXR then induces the release of fibroblast growth factor 19 (FGF19) into the portal blood, which travels to the liver.   3. In the liver, FGF19 binds to the FGFR4/β-Klotho receptor on hepatocytes, inhibiting CYP7A1 activity, leading to a decrease in new bile acid synthesis.   4. Hepatocytes take up bile salts from the portal blood through NTCP, and these bile salts are resecreted into bile via BSEP, allowing for a continuous recycling process.

COMMON METABOLIC FATES FOR UROBILINOGEN

  • Most urobilinogen is converted into stercobilin, which contributes to the brown color of feces, and a small portion is reabsorbed into the portal blood.

  • A minor fraction enters systemic circulation, reaching the kidneys, where it is converted to urobilin, contributing to the yellow color of urine.