16 - Heme catabolism Flashcards
What two things does the body have to deal with during heme catabolism?
- handling the hydrophobic products of porphyrin ring cleavage
- retention, safe mobilization, and re-utilization of iron
What is ferrous iron?
Fe2+ (an extremely reactive molecule, generating ROS and promoting oxidative stress)
Describe heme… how is it toxic for the vascular endothelium?
- hydrophobic (can intercalate into lipid bilayers, altering its fluidity/permeability)
- can generate ROS
- participates in the oxidation of lipid membrane components/cause lipid peroxidation
- oxidative stress can cause endothelial activation responsible for vaso-occlusive events and thrombus formation
How is hemoglobin toxic for the vascular endothelium?
- Free Hb binds NO, reducing NO bioavailability
- NO from the endothelium normally diffuses to adjacent smooth muscle cells, causing relaxation (via cGMP)
- Hb dysregulation of the dilator/constrictor balance can lead to severe vasoconstriction and HTN (a common feature of hemolysis)
What are the 2 main mechanisms of hemolysis?
- intravascular (10-20%)
- extravascular (80-90%)
Where does extravascular hemolysis primarily take place?
Macrophages in the spleen (red pulp cells) and liver (kupfer cells)
**either full phagocytosis or partial ingestion via scission
What is haptoglobin?
- a tetrameric glycoprotein (3 isoforms; Hp 1-1, 2-1, and 2-2)
- Hp 2-2 over-represented in autoimmune and inflammatory diseases
- an “acute phase” glycoprotein that binds free Hb
- levels increase during acute inflammation and in response to neoplastic inflammatory cytokines
- produced mostly in the liver by hepatocytes and secreted into blood circulation
- clinical marker of hemolysis (levels decrease)
Describe heme degradation via haptoglobin
- haptoglobin functions as an antioxidant by binding Hb dimers and sequestering them (prevents release of free heme and oxidative damage of free iron)
- haptoglobin-Hb complex cannot pass through glomerular filter (good! helps us conserve iron!)
- non-renal elimination required (complex binds CD163 and is consumed by macrophages by receptor-mediated endocytosis)
What is the CD163 scavenger receptor?
- type I transmembrane glycoprotein that binds the haptoglobin-Hb complex
- expression is restricted to the monocyte/macrophage lineage
- recycles after endocytosis from the early endocomes back to the plasma membrane
What happens when haptoglobin’s buffering capacity is overwhelmed?
Hb undergoes rapid conversion to metHb, releasing heme
**hemopexin binds heme for degradation
Describe hemopexin
- an “acute phase” glycoprotein that binds free heme
- produced mostly in the liver by hepatocytes and secreted into blood circulation
- levels markedly increase during acute phase inflammation in response to inflammatory cytokines and during heme overload
What is the CD91 scavenger receptor?
- type I transmembrane glycoprotein that is also known as the LDL receptor related protein (LRP1)
- binds the hemopexin-heme complex
- expressed in numerous cell types
- recycles between early endosomes and the plasma membrane
Describe extravascular hemolysis
- macrophages sense senescent (aging, 120+ days) RBCs and phagocytose them
- ~80% of heme catabolism occurs from senescent RBCs (20% from immature RBC turnover)
- Hb is broken down into heme in the lysosome
- heme is transferred to the cytosol where it’s catabolized by heme oxygenase 1 (HO-1)
What is bilirubin?
- breakdown product of heme
- an orange pigment that is a potentially toxic waste product (generally harmless because of binding to serum albumin)
- inherited disorders of billirubin metabolism lead to hyperbilirubinemia (resulting in jaundice or icterus)
What are the steps of heme catabolism that take place in the macrophage?
-
heme (tetracyclic porphyrin ring) cleaved by heme oxygenase (HO)
*requires NADPH and electrons from CYPOR
*results in the release of iron and CO
*generates linear biliverdin (green!) - biliverdin converted to bilirubin (orange!) by biliverdin reductase (double bonds moved around)
