Biology:Haptoglobin

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
A model of α,β-hemoglobin/haptoglobin hexamer complex. There are 2 α,β-hemoglobin dimers depicted: one space filling model (yellow/orange), and one ribbon model (purple/blue). Each is bound by a haptoglobin molecule (both haptoglobin molecules are shown in pink, with one as a space filling model and one as a ribbon model).

Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the HP gene.[1][2] In blood plasma, haptoglobin binds with high affinity to free hemoglobin[3] released from erythrocytes, and thereby inhibits its deleterious oxidative activity. Compared to Hp, hemopexin binds to free heme.[4] The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system (mostly the spleen).

In clinical settings, the haptoglobin assay is used to screen for and monitor intravascular hemolytic anemia. In intravascular hemolysis, free hemoglobin will be released into circulation and hence haptoglobin will bind the hemoglobin. This causes a decline in haptoglobin levels.

The protein was discovered as a "plasma substance" in 1938 by French biochemists Max-Fernand Jayle and Michel Polonovski.[5][6]

Function

Hemoglobin that has been released into the blood plasma by damaged red blood cells has harmful effects. The HP gene encodes a preproprotein that is processed to yield both alpha and beta chains, which subsequently combines as a tetramer to produce haptoglobin. Haptoglobin functions to bind the free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin.[7]

The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, CD163.[3] Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization.[3]

Hp has hemoglobin-independent immunomodulatory functions. It dampens lipopolysaccharide-induced cytokine expression.[8] Lipopolysaccharides directly bind to Hp, which, due to the high abundance of Hp in serum, results in their buffering and shielding from toll-like receptor 4. Functionally, this results in delayed activation of the NF-κB pathway.[9]

Difference from hemopexin

When hemoglobin is released from RBCs within the physiologic range of haptoglobin, the potential deleterious effects of hemoglobin are prevented. During hyper-hemolytic conditions or with chronic hemolysis, haptoglobin is depleted and hemoglobin readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric (Fe3+-bound) hemoglobin. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein that is able to bind heme with high affinity. It sequesters heme in an inert non-toxic form and transports it to the liver for catabolism and excretion.[3]

Synthesis

Haptoglobin is produced mostly by hepatic cells but also by other tissues such as skin, lung and kidney. In addition, the haptoglobin gene is expressed in murine and human adipose tissue.[10]

Haptoglobin had been shown to be expressed in adipose tissue of cattle as well.[11]

Structure

Haptoglobin, in its simplest form, consists of two alpha and two beta chains, connected by disulfide bridges. The chains originate from a common precursor protein, which is proteolytically cleaved during protein synthesis.

Hp exists in two allelic forms in the human population, so-called Hp1 and Hp2, the latter one having arisen due to the partial duplication of Hp1 gene. Three genotypes of Hp, therefore, are found in humans: Hp1-1, Hp2-1, and Hp2-2. Hp of different genotypes have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder. Allele 2 encodes for two multimerization domains. This results in oligomer formation in carriers of allele 2.[12] The frequency of the short allele varies between 7% and 70% depending on racial origin.[13] It is unclear which evolutionary advantage is conferred by the longer allele; strikingly, a similar partial duplication independently arose much earlier in a precursor of ruminants. Ruminants exclusively express oligomeric haptoglobin.[14]

In other species

Hp has been found in all mammals studied so far, some birds, e.g., cormorant and ostrich but also, in its simpler form, in bony fish, e.g., zebrafish. Hp is absent in at least some amphibians (Xenopus) and neognathous birds (chicken and goose).

Clinical significance

Mutations in this gene or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy,[15] the incidence of coronary artery disease in type 1 diabetes,[16] Crohn's disease,[17] inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease,[18] and a reduced incidence of Plasmodium falciparum malaria.[19]

Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body,[4] haptoglobin levels will be decreased in case of intravascular hemolysis or severe extravascular hemolysis. In the process of binding to free hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis. It is theorized that, because of this, haptoglobin has evolved into an acute-phase protein. HP has a protective influence on the hemolytic kidney.[20][21]

The different haptoglobin phenotypes differ in their antioxidant, scavenging,[22] and immunomodulatory properties. This aspect of haptoglobin may gain importance in immune suppressed conditions (such as liver cirrhosis) and the various phenotypes may result in different susceptibility levels towards bacterial infections.[23]

Some studies associate certain haptoglobin phenotypes with the risk of developing hypertension in diabetes[24] and schizophrenia.[25]

Test protocol

Measuring the level of haptoglobin in a patient's blood is ordered whenever a patient exhibits symptoms of anemia, such as pallor, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a reticulocyte count and a peripheral blood smear. It can also be ordered along with a direct antiglobulin test when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia. Also, it may be ordered in conjunction with a bilirubin.

Interpretation

A decrease in haptoglobin can support a diagnosis of hemolysis, especially when correlated with a decreased hemoglobin, and hematocrit, and also an increased reticulocyte count. Low haptoglobin levels occur regardless of the site and mechanism of haemolysis (intravascular and splenic/"extravascular") [26]

If the reticulocyte count is increased, but the haptoglobin level is normal, this argues against haemolysis, and suggests a bone marrow response to blood loss. If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most likely not due to hemolysis. Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate advanced liver damage, as the liver is the major site of production of haptoglobin.

As haptoglobin is an acute-phase protein, any inflammatory process (infection, injury, allergy, etc.) may increase the levels of plasma haptoglobin, but patients with haemolysis usually have low haptoglobin regardless of the presence of inflammation [27]

See also

References

  1. ↑ "Biological functions of haptoglobin--new pieces to an old puzzle". European Journal of Clinical Chemistry and Clinical Biochemistry 35 (9): 647–654. September 1997. PMID 9352226. 
  2. ↑ "Haptoglobin: function and polymorphism". Clinical Laboratory 46 (11–12): 547–552. 2000. PMID 11109501. 
  3. ↑ 3.0 3.1 3.2 3.3 "Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development". Frontiers in Physiology (Frontiers Media SA) 5: 415. 2014-10-28. doi:10.3389/fphys.2014.00415. PMID 25389409. 
  4. ↑ 4.0 4.1 "Intravascular hemolysis". http://eclinpath.com/hematology/anemia/mechanisms-of-anemia/intravascular-hemolysis-new/. 
  5. ↑ "Haptoglobin testing in hemolysis: measurement and interpretation". American Journal of Hematology 89 (4): 443–447. April 2014. doi:10.1002/ajh.23623. PMID 24809098. 
  6. ↑ "Haptoglobins" (in en). New England Journal of Medicine 266 (11): 569–570. 1962-03-15. doi:10.1056/NEJM196203152661115. ISSN 0028-4793. http://www.nejm.org/doi/abs/10.1056/NEJM196203152661115. 
  7. ↑ "Entrez Gene: HP". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3240. 
  8. ↑ "Haptoglobin dampens endotoxin-induced inflammatory effects both in vitro and in vivo". Immunology 114 (2): 263–271. February 2005. doi:10.1111/j.1365-2567.2004.02071.x. PMID 15667571. 
  9. ↑ Zein, Laura; Grossmann, Josina; Swoboda, Helena; Borgel, Christina; Wilke, Bernhard; Awe, Stephan; Nist, Andrea; Stiewe, Thorsten et al. (2022). "Haptoglobin buffers lipopolysaccharides to safeguard against aberrant NFκB activation". BioRXiv (Preprint). doi:10.1101/2022.11.22.516855. https://doi.org/10.1101/2022.11.22.516855. 
  10. ↑ "Adipokines: inflammation and the pleiotropic role of white adipose tissue". The British Journal of Nutrition 92 (3): 347–355. September 2004. doi:10.1079/BJN20041213. PMID 15469638. 
  11. ↑ "Bovine haptoglobin as an adipokine: serum concentrations and tissue expression in dairy cows receiving a conjugated linoleic acids supplement throughout lactation". Veterinary Immunology and Immunopathology 146 (3–4): 201–211. May 2012. doi:10.1016/j.vetimm.2012.03.011. PMID 22498004. 
  12. ↑ "Biological functions of haptoglobin--new pieces to an old puzzle". European Journal of Clinical Chemistry and Clinical Biochemistry 35 (9): 647–654. September 1997. PMID 9352226. 
  13. ↑ "Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases". International Journal of Laboratory Hematology 29 (2): 92–110. April 2007. doi:10.1111/j.1751-553X.2007.00898.x. PMID 17474882. 
  14. ↑ "Convergent evolution of human and bovine haptoglobin: partial duplication of the genes". Journal of Molecular Evolution 65 (4): 373–379. October 2007. doi:10.1007/s00239-007-9002-3. PMID 17922076. Bibcode: 2007JMolE..65..373W. 
  15. ↑ "In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease". Vascular Health and Risk Management 1 (1): 19–28. 2005. doi:10.2147/vhrm.1.1.19.58930. PMID 17319095. 
  16. ↑ "Haptoglobin phenotypes in health and disorders". American Journal of Clinical Pathology 121 (Suppl): S97-104. June 2004. doi:10.1309/8GLX5798Y5XHQ0VW. PMID 15298155. 
  17. ↑ "Haptoglobin polymorphisms are associated with Crohn's disease, disease behavior, and extraintestinal manifestations in Hungarian patients". Digestive Diseases and Sciences 52 (5): 1279–1284. May 2007. doi:10.1007/s10620-006-9615-1. PMID 17357835. 
  18. ↑ "The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 147B (2): 216–222. March 2008. doi:10.1002/ajmg.b.30593. PMID 17918239. 
  19. ↑ "Iron metabolism and malaria". Food and Nutrition Bulletin 28 (4 Suppl): S524–S539. December 2007. doi:10.1177/15648265070284S406. PMID 18297891. 
  20. ↑ "The protective influence of haptoglobin on hemoglobinuric kidney. I. Bioch- emical and macroscopic observations". Folia Haematologica 90 (1): 82–91. 1968. PMID 4176393. 
  21. ↑ "[Pathogenesis of kidney hemolysis]" (in de). Bruns' Beiträge für Klinische Chirurgie 217 (7): 661–665. December 1969. PMID 5404273. 
  22. ↑ Olaniyan, O. O; Odewusi, O. O; Osadolor, H. B (2021). "Oxidative protein modification and chromosomal instability among type 2 diabetics in Osogbo, Nigeria. .". Alexandria Journal of Medicine (TAJM) 57: 168–176. doi:10.1080/20905068.2021.1935123. 
  23. ↑ "Phenotypic polymorphism of haptoglobin: a novel risk factor for the development of infection in liver cirrhosis". Human Immunology 72 (4): 348–354. April 2011. doi:10.1016/j.humimm.2011.01.008. PMID 21262313. 
  24. ↑ Odewusi Odeyinka O; Ogberetitinor Ofejiro B; Ijeh Wendy A; Obadire Olalere S; Olaniyan Olayinka O (July–September 2023). "Evaluation Of Neuronal Inflammation And Oxidative Dna Damage In Different Haptoglobin Phenotypes Of A Nigerian Type-2 Diabetes Population". Journal of Krishna Institute of Medical Science University 12 (3): 50–62. https://www.jkimsu.com/jkimsu-vol12no3/JKIMSU,%20Vol.%2012,%20No.%203,%20July-September%202023%20Page%2050-62.pdf. 
  25. ↑ Gene Overview of All Published Schizophrenia-Association Studies for HP - SzGene database at Schizophrenia Research Forum.
  26. ↑ "Influence of clinical factors on the haemolysis marker haptoglobin". European Journal of Clinical Investigation 36 (3): 202–209. March 2006. doi:10.1111/j.1365-2362.2006.01617.x. PMID 16506966. 
  27. ↑ "Influence of clinical factors on the haemolysis marker haptoglobin". European Journal of Clinical Investigation 36 (3): 202–209. March 2006. doi:10.1111/j.1365-2362.2006.01617.x. PMID 16506966. 

Further reading

External links



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