Phylogenetic origin of hepcidin
Paolo sent me this comment/question, which I thought would be great to post to the forum.
"We had a number of very interesting reviews on the function, regulation and structure of the human and mouse hepcidin, even of the camel one, but we know very little of its phylogenetic origin. For example there is a large number of papers on fish hepcidin, mostly linked to inflammation, infection, but few, if any, regarding iron homeostasis.
Briefly, is it known when first occurred the encounter between hepcidin and ferroportin with the ensuing regulatory consequences?"
Well, iron community, does anyone have any thoughts on this?
Ferroportin has been found in bacteria (Bellovibrio bacteriovorus), red and green algae and diatoms, plants and animals. My search for hepcidin only found it in vertebrates, starting with bony fishes, see below:
Details of fishes:
One strange things is birds where hepcidin is not documented except in the Tibetan Ground-Tit [ Pseudopodoces humilis ] despite the presence of ferroportins with intact hepcidin-binding sites. I have lined up the ferroportins in the databases and looked for ferroportin C326 (human equivalent) as evidence of the hepcidin-binding potential and this also first appears in fish.
One possibility is that animals only need hepcidin if they have abundant erythrocytes with a relatively short lifespan, so a high iron turnover. As best as I can determine this first appears in bony fish. There are hemoglobin-containing cells in lower animals but their density is lower than in fish and they may also be replicating directly, so may not need iron recycling.
I would be interested in others thoughts on this, I must admit that my analysis was never as deep as it should have been.
Minor correction, there is another bird with a good hepcidin sequence, Lonchura striata domestica (society finch). They both belong to Passeriformes and so are relatively closely related. The sequences are real because they are close to reptile sequences and to each other.
Organism Blast Name Score Number of Hits Description
.cellular organisms 151
..Eukaryota eukaryotes 142
...Opisthokonta eukaryotes 137
....Bilateria animals 132
.....Euteleostomi vertebrates 131
......Tetrapoda vertebrates 17
.......Sauria vertebrates 10
........Archelosauria vertebrates 6
.........Archosauria vertebrates 5
..........Passeriformes birds 2
...........Pseudopodoces humilis birds 162 1 Pseudopodoces humilis hits
...........Lonchura striata domestica birds 65.9 1 Lonchura striata domestica hits
..........Crocodylus siamensis crocodiles 62.4 1 Crocodylus siamensis hits
..........Alligator mississippiensis vertebrates 60.5 2 Alligator mississippiensis hits
.........Chrysemys picta bellii turtles 65.9 1 Chrysemys picta bellii hits
........Pogona vitticeps lizards 70.9 1 Pogona vitticeps hits
........Python bivittatus snakes 49.7 1 Python bivittatus hits
........Thamnophis sirtalis snakes 47.8 1 Thamnophis sirtalis hits
........Protobothrops mucrosquamatus snakes 46.6 1
Ok, a little more update. There is an unannotated but clearly hepcidin-related sequence in a shark (cartilaginous fish) Callorhinchus milii so that takes us further back. Could not find anything in the lamprey genome which would be another step back.
The shark also has two ferroportin-like sequences (similar to the well-studied zebrafish ferroportin) one of which has the key cysteine required for hepcidin binding (equivalent to C326 in humans). I highlighted these cysteines in the context of the neighboring segment in the attached file.
So the shark looks good for having hepcidin and a hepcidin-binding ferroportin (as well as another ferroportin that does not bind hepcidin)
Ok, I will stop now... Here is a corrected TBLASTN using the shark ferroportin with the equivalent of C326 in humans. It was blasted against cartilagenous fish and tunicates (pre-vertebrates). As you can see, there are indeed two ferroportins each in the two shark species, one with and one without cysteine (my previous post highlighted the wrong cysteine). The tunicate has only one ferroportin and it does not have a C326 equivalent cysteine. So the trail goes cold here...
If animals only need hepcidin if they have abundant erythrocytes with a relatively short lifespan, then birds should have hepcidin. Birds have abundant RBCs with shorter lifespans than those in mammals (i.e., 25-45 days in birds). To me, it seems that the high iron turnover in birds would not benefit from hepcidin. Also, bird diets are often low in bioavailable iron, so this would provide positive selection pressure for birds with low/no hepcidin.
Maybe animals only need hepdicin if they have a diet high in bioavailable iron.
Some birds have a relatively high iron diet, i.e. if they are predatory carnivores or eat worms or insects. Even chickens should have a diet that has plenty of iron in it, compared to mice that do not eat worms, as far as I know. I think it would be worthwhile to clear this up by studying iron homeostasis in chickens. I have tried to get Glenn Zhang at Oklahoma State interested. He is busy with another project but promised to get back to me.
This is a great idea, Tom. It seems that there has been a fair amount of research (done quite a while ago) on iron and iron supplements in chicken nutrition. One study I found (attached) gave broiler chicks graded doses of supplemental ferrous sulfate. Hepatic iron concentrations increased with increasing iron (up to a point), but splenic iron concentrations did not change.
Thanks to Tom for the interesting data.
I imagine that since the bone morphogenetic proteins are present in all these species, it is reasonable to assume that hepcidin/ferroportin axis is iron regulated and plays a role in systemic iron control in fishes and in some birds. Although this should be demonstrated. In addition to birds maybe some interesting models could be the cold fishes that lost hemoglobin since live in waters rich in oxygen.
In this discussion I would like to recall the paper by: Neves et al. Hamp1 but not Hamp2 regulates ferroportin in fish with two functionally distinct hepcidin types. Sci Rep. 2017 Nov 1;7(1):14793.
... Contrary to humans, where a single hepcidin exists, many fish have two functionally distinct hepcidin types, despite having a single ferroportin gene. This raises the question of whether ferroportin is similarly regulated by the iron regulator Hamp1 and the antimicrobial Hamp2. In sea bass (Dicentrarchus labrax), iron overload prompted a downregulation of ferroportin, associated with an upregulation of hamp1, whereas an opposite response was observed during anemia, with no changes in hamp2 in either situation. During infection, ferroportin expression decreased, indicating iron withholding to avoid microbial proliferation. In vivo administration of Hamp1 but not Hamp2 synthetic peptides caused significant reduction in ferroportin expression, indicating that in teleost fish with two hepcidin types, ferroportinactivity is mediated through the iron-regulator Hamp1, and not through the dedicated antimicrobial Hamp2. Additionally, in vitro treatment of mouse macrophages with fish Hamp1 but not Hamp2 caused a decrease in ferroportin levels. These results raise questions on the evolution of hepcidin and ferroportin functional partnership and open new possibilities for the pharmaceutical use of selected fish Hamp2 hepcidinsduring infections, with no impact on iron homeostasis.