Handling heme

Comment on Hvidberg et al, page 2572

Hemopexin is a plasma protein that binds heme with high affinity. Hvidberg and colleagues report here that hemopexin-heme is cleared from the circulation by the low-density lipoprotein receptor-related protein (LRP)/CD91, a multifunctional scavenger. This helps to define a biologically important pathway for eliminating potentially toxic-free heme.

As a prosthetic group bound to various proteins, the small molecule heme has big functions, including oxygen binding, electron transport, catalysis, and intracellular signaling.¹  In contrast, free heme is a potent oxidant causing cytotoxicity and inflammation. Circulating heme released from proteins after cell breakdown is linked to various disorders including atherosclerosis, renal injury, and central nervous system (CNS) damage.²  This is particularly important in hemorrhage and hemolysis (both acute and chronic) because erythrocyte hemoglobin is an abundant heme source. Haptoglobin and hemopexin bind hemoglobin and heme, respectively, to limit their reactivities and facilitate their catabolism via receptor-mediated endocytosis. In 2001, Kristiansen and colleagues identified the monocyte/macrophage protein CD163 as a scavenger receptor for hemoglobin-haptoglobin. Now, the same group demonstrates that hemopexin-heme is removed from circulation by the low-density lipoprotein (LDL) receptor-related protein (LRP/CD91), a multifunctional scavenger expressed in brain, placenta, liver, and macrophage/monocytes. Together, these studies define an important set of pathways that protect against noxious free heme (see figure) and identify new areas of investigation for heme biology.

By virtue of its restricted expression pattern, LRP/CD91 is predicted to deliver hemopexin-heme into specific tissues. This has potential biological consequences. LRP/CD91 transports its cargo to lysosomes where hemopexin is degraded, presumably releasing intact heme. Inside cells, heme regulates gene expression by modulating the DNA binding activity and subcellular localization of transcription factors.³  One consequence is induction of heme oxygenase-1 (HO-1), which degrades heme into metabolites with potent antioxidant and anti-inflammatory activities.⁴  The current study found that hemopexinheme taken up by LRP/CD91 induces HO-1 in monocytes, which could inhibit their inflammatory functions. Heme recruitment by LRP/CD91 could induce HO-1 and its beneficial effects in other tissues as well. The CNS is of interest because free heme is implicated in the pathogenesis of both chronic neurodegenerative disorders and acute tissue damage after intracranial hemorrhage.⁵  Moreover, hemopexin is abundant in cerebrospinal fluid, and LRP/CD91 is expressed in neurons. Hence, heme uptake by LRP/CD91 could protect neurons by inducing HO-1. Another issue is whether heme brought into cells by LRP/CD91 could remain intact and be recycled directly into proteins, for example, in hepatocytes, where LRP is expressed and protein heme requirements are relatively high.

LRP/CD91 is a transmembrane protein with numerous functions, including plasma protein scavenging, intracellular signaling, and neurotransmission. Hemopexin-heme binding could affect these functions, particularly in pathological states that saturate the receptor. For example, LRP/CD91 removes plasma proteases and cofactors involved in blood coagulation. Modulation of LRP function by high levels of hemopexin-heme may influence this process to impact clot formation or dissolution. In principle, this mechanism could contribute to thrombophilia associated with many hemolytic disorders.⁶ 

Finally, genetic variations in heme uptake pathways could contribute to common multifactorial diseases. Polymorphisms in haptoglobin affect vascular complications in diabetics, probably due to functional differences in neutralizing the oxidative effects of globin-associated heme.⁷  It is also possible that genetic variations in heme metabolism by the newly defined hemopexin-heme-LRP/CD91 pathway affect susceptibility to vascular and nervous system disorders that are perpetuated by oxidative injury. ▪