3 The tight control of heme synthesis vs heme degradation is essential because free heme is a pro-oxidant and toxic molecule.4 and 5 Both heme synthesis and heme degradation are tunely regulated by heme itself. Heme controls Alas1 transcription, the stability of Alas1 messenger RNA (mRNA) and the accumulation of the mature protein in the mitochondrion. 6, 7 and 8 On the opposite side, heme controls Ho-1 gene expression by removing the transcriptional repressor BACH1 from its promoter. 9 The pool of heme that exerts

this control, selleck products the so-called “free” or “regulatory” heme pool, is determined by a balance between heme synthesis and degradation and because of its small size, dynamic GSK1120212 cell line properties, and ability to readily exchange with heme-containing proteins, reflects the overall status of cellular heme content. 10 Recently, heme export through the cell-surface transporter feline leukemia virus subgroup C cellular receptor 1a (Flvcr1a) was proposed as an additional control step to prevent the intracellular accumulation of heme.11 and 12Flvcr1 gene is essential for erythropoiesis

and systemic iron homeostasis. 12 It encodes for 2 proteins, FLVCR1a and FLVCR1b, expressed at the plasma membrane and on the mitochondrion, respectively. FLVCR1a belongs to the SLC49 family of the major facilitator superfamily of transporters with 12 hydrophobic transmembrane domains. 12 and 13 FLVCR1b is a shorter protein with only 6 transmembrane domains, supposed to homodimerize to form a functional transporter. 13 We recently demonstrated a crucial role for FLVCR1b in the last step of heme biosynthetic pathway, ie, heme export from mitochondria. 13 On the other hand, FLVCR1a exerts its heme export activity at the plasma membrane and avoids intracellular heme loading. Previous studies showed that FLVCR1a-mediated heme export in macrophages prevents heme-derived iron accumulation

after erythrophagocytosis. 14 Consistently, silencing of Flvcr1a in HeLa cells results in cytosolic heme loading, HO-1 induction, and oxidative stress. Finally, Flvcr1a C59 deletion in mice causes embryo lethality due to extended hemorrhages. 13 The liver is one of the body compartments with the highest heme rate synthesis. More than 50% of the heme synthesized in the liver is committed to the synthesis of cytochromes P450 (CYPs),15 the major enzymes involved in drug metabolism.16 As the prosthetic moiety of all CYPs, heme is responsible for the catalytic activity of these enzymes. In addition, the free heme pool also regulates CYP protein synthesis and disposal.10 Here we show that Flvcr1a function in hepatocytes is critical for the maintenance of a heme pool that controls CYP expression and activity.