Metabolism of Vitamin A

1. Forms and Nomenclature

2. Dietary Sources

• Preformed vitamin A (retinyl esters): liver, fish, eggs, milk, butter - animal-origin foods only
• Provitamin A carotenoids: yellow/orange/green vegetables (carrots, squash, spinach) - contribute ~30% of dietary vitamin A
• β-carotene is the most important provitamin A in the diet

• 1 Retinol Activity Equivalent (RAE) = 1 μg all-trans-retinol = 12 μg dietary β-carotene = 24 μg α-carotene or β-cryptoxanthin
• 1 IU = 0.3 μg retinol; 1 μg retinol = 3.33 IU

3. Absorption

• Bile (for emulsification)
• Pancreatic enzymes
• Some dietary antioxidant activity

• Dietary retinyl esters are hydrolyzed to free retinol
• β-Carotene is cleaved by carotene dioxygenase at the central double bond, yielding retinaldehyde, which is then reduced to retinol
• A second isoform of carotene dioxygenase performs asymmetric cleavage, producing apo-carotenals → oxidized to retinoic acid only (cannot serve as retinol source)
• Retinol is then re-esterified in the enterocyte

4. Transport from Gut to Liver

• Retinyl esters are packaged into chylomicrons in intestinal epithelial cells
• Chylomicrons travel via lymphatics into the bloodstream
• Retinyl esters are taken up by the liver via the apolipoprotein E (ApoE) receptor

5. Hepatic Storage

• >90% of body vitamin A reserves are stored in the liver
• Stored predominantly as retinyl esters in perisinusoidal stellate (Ito) cells
• These reserves are sufficient to support body needs for at least 6 months in healthy individuals

6. Transport from Liver to Peripheral Tissues

1. Retinyl esters are hydrolyzed back to free retinol
2. Retinol binds to Retinol-Binding Protein (RBP), which is synthesized in the liver
3. The retinol-RBP complex then binds to transthyretin (formerly prealbumin) in the circulation, forming a trimolecular complex

This trimolecular complex is important because it:

• Prevents retinol from being filtered by the kidney glomerulus
• Protects the body from retinol toxicity
• Allows uptake via specific cell-surface RBP receptors

7. Intracellular Handling

• Sequestering agents
• Transporting agents
• Co-ligands for enzymatic reactions

• Stored as retinyl ester in peripheral tissues
• Oxidized to retinaldehyde (by retinol dehydrogenases)
• Further oxidized to retinoic acid (irreversible)

8. The Visual Cycle (Retinaldehyde Function)

1. In the pigment epithelium: all-trans-retinol → isomerized to 11-cis-retinol → oxidized to 11-cis-retinaldehyde
2. 11-cis-retinaldehyde binds to a lysine residue on opsin (via Schiff base linkage) → forms rhodopsin (rods) or iodopsin (cones)
3. Light absorption causes isomerization of retinaldehyde from 11-cis → all-trans configuration, and a conformational change in opsin
4. This generates a series of intermediates: Photorhodopsin → Bathorhodopsin → Lumirhodopsin → Metarhodopsin I → Metarhodopsin II → Metarhodopsin III
5. Metarhodopsin II activates transducin (a G-protein), which activates phosphodiesterase, converting cGMP → 5'GMP
6. Reduced cGMP closes Na⁺ channels → hyperpolarization → nerve impulse
7. Final hydrolysis releases all-trans-retinaldehyde + opsin (bleached state)
8. All-trans-retinaldehyde is recycled back through the pigment epithelium to regenerate 11-cis-retinaldehyde

9. Retinoic Acid and Gene Regulation

• RAR/RXR heterodimers bind to Retinoic Acid Response Elements (RAREs) on DNA
• Can either stimulate or repress gene transcription depending on context
• Target genes include: growth factor receptors, tumor suppressor genes, secreted proteins

• RXR + RAR → regulates differentiation
• RXR + Vitamin D Receptor (VDR) → bone metabolism
• RXR + Thyroid Hormone Receptor → thyroid response
• RXR + PPARs → fatty acid/carbohydrate metabolism, adipogenesis, insulin sensitivity

10. Metabolic Effects of Retinoids

• Inhibit adipogenesis and stimulate lipid breakdown
• RXR-PPAR heterodimers mediate effects on adipogenesis (this is also the pathway targeted by thiazolidinediones like rosiglitazone)
• Enhance resistance to infection by regulating differentiation of immune cells (T cells, natural killer cells, phagocytes)
• Play a role in iron utilization and humoral immunity

11. Catabolism and Excretion

• Retinoic acid undergoes hepatic oxidation (via CYP enzymes) to more polar metabolites
• These are conjugated (often as glucuronides) and excreted in bile and urine
• Retinol oxidation to retinoic acid is irreversible - cells cannot convert retinoic acid back to retinol or retinaldehyde
• Retinaldehyde ↔ retinol conversion is reversible

12. Summary Flow

Diet
├── Retinyl esters (animal foods)
│   └── Hydrolysis in gut → Retinol
└── β-Carotene (plant foods)
    └── Carotene dioxygenase in intestine → Retinaldehyde → Retinol

Intestine → Retinyl esters → Chylomicrons → Lymph → Blood → Liver (ApoE receptor)

Liver (Ito cells):
  ├── Storage as retinyl esters (>90% of body stores)
  └── Secretion: Retinol + RBP + Transthyretin → Circulation → Peripheral cells

Peripheral cells:
  Retinol
  ├── → Retinaldehyde (reversible, retinol dehydrogenase)
  │   └── → 11-cis-Retinaldehyde → Rhodopsin (VISION)
  └── → Retinoic acid (irreversible)
      └── → Nuclear RAR/RXR receptors → Gene transcription
              (differentiation, growth, immunity, lipid metabolism)