NS 3410 CC1- Receptor Mediated Endocytosis

Disorders of Fe homeostasis are among?

most common diseases in humans

Iron is highly reactive so needs to be transported bound to?

a carrier protein

Old (senescent) red blood cells (RBC”s) lose their flexibility, get trapped in the ____, are catabolized, the Fe is _____

spleen; reutilized

What are 4 key cells regulate Fe:

1. Macrophage

2. Enterocyte

3. Hepatocyte

4. Erythroid precursors

What stimulates Erythropoietin

hypoxia; inadequate supply of oxygen to the body's tissues

What does “erytho” mean?

red

What does “poietin” mean?

form

Where is erythropoietin made?

kidney

What does erythropoietin regulate? What does it Bind?

RBC synthesis; EPO receptors

Where is erythroferrone made in? What is made by? What does it bind to?

bone and spleen; erythroblast; binds to BMPs

What does Erythroferrone inhibit?

hepcidin

Where is hepcidin made in? What is it made by? What does it bind?

1. Made in the liver

2. Made by hepatocytes

3. Binds to ferroprotein (receptor)

Hepcidin prevents what? What does hepcidin block?

1. Prevents Fe absorption

2. Blocks iron release from stores

What unique aspect of Fe homeostasis predisposes humans to Fe overload?

there is no regulatable way to get rid of excess Fe that gets into the body; i.e no way to excrete excess Fe

• Must balance the amount of iron absorbed as a function of body Fe demand

Iron must be in ______ to be absorbed but it ingested mainly as ______?

ferrous form (Fe2+); ferric (Fe3+)

In ENTEROCYTE Fe3+ reduced to Fe2+ by?

ferric reductase (Dcytb-duodenal cytochrome b)

Fe imported into cell by transmembrane protein ….?

DMT1; Divalent Metal Transporter

Once in the cell Fe enters the?

labile iron pool (LIP) and be stored as ferritin if not needed

If Fe is needed it is exported as Fe2+ by?

Ferroportin; ferroportin is the only iron export protein for non-heme Fe

Fe2+ (ferrous Fe) is oxidized to Fe3+ by?

Hephaestin (ferroxidase)

Fe must be in what form to bind to TfR?

Ferric 3+

Fe3_ binds to specific serum protein _____ to keep it in a non-reactive state

transferrin

What does “entero” mean

gut

What does “cyte”

cell

Iron uptake- Enterocyte

Iron uptake– Enterocyte Pt2

What unique property of enterocytes compared to the macrophage or hepatocyte makes this cell type effective at maintaining Fe balance?

Enterocyte physiology is unique compared to hepatocytes or macrophages. These cells turn over every 3 days and old cells are sloughed into GI lumen and lost in feces. Iron that stored as ferritin in the enterocyte would be lost from the body every 3 days. Liver cells must store iron indefinitely which can cause damage if too much is accumulated.

What does “em” mean?

blood

Once Fe is absorbed into the body what do target tissues need to express in order to capture Fe from the circulation?

Transferrin receptor to capture transferrin bound Fe by receptor mediated endocytosis cell must have receptor for Tf=TfR

What tissue likely has the highest expression of this?

Erythroid tissue- tissue that make RBC’s

• Erythroid tissue is found in red bone marrow

Cellular Fe uptake- Receptor Mediated endocytosis: Iron is exported out of endosome by? Only after being converted from?

DMT1; converted from Ferric Fe to Ferrous Fe by Steap 3 ferrireductase enzyme

Summary

Transferrin is a very?

abundant plasma protein

Transferrin saturation normally about 30%; Transferrin bound Fe is the primary?

physiological source available to most cells under normal Fe status conditions

Cells regulate update of Tf-fe by altering the expression of?

TfR1

If too much Fe in circulation (Transferrin saturation excessive) some Fe can also bind to what 3 things?

1. Citrate

2. Albumin

3. Other low molecular weight compounds

   • non-transferrin bound Fe (NTBI)

NTBI in the plasma is taken up most avidly by the?

liver

• to a lower extent by the pancreas and heart

Excess uptake of the NTBI form can cause?

oxidant mediated cellular injury

Laboratory Data: Microcytic, hypochromic anemia:

7. How can you have both anemia and tissue Fe overload?

Some cells (like erythroid tissue) rely only on TfR to take up Fe from the blood. Erythroid tissues have TfR but if there is no Tf-Fe in blood they can’t scavenge Fe from blood. This leads to low Hb concentrations (anemia) and high NTBI (the Fe must go somewhere since we can’t excrete it). Tissues like liver, heart pancreas, can take up NTBI so they develop Fe overload.

Different tissues express different proteins on their membranes giving specificity of functions in different tissues / organs in the body

Production of heme in erythroid tissue requires?

Tf-Fe

NTBI cannot be used by erythroid tissue to form?

heme

NTBI can’t upregulate?

hepcidin

Tf-Fe regulates hepcidin via?

TfR