Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450

Abstract

Background & AimsThe liver has one of the highest rates of heme synthesis of any organ. More than 50% of the heme synthesized in the liver is used for synthesis of P450 enzymes, which metabolize exogenous and endogenous compounds that include natural products, hormones, drugs, and carcinogens. Feline leukemia virus subgroup C cellular receptor 1a (FLVCR1a) is plasma membrane heme exporter that is ubiquitously expressed and controls intracellular heme content in hematopoietic lineages. We investigated the role of Flvcr1a in liver function in mice.MethodsWe created mice with conditional disruption of Mfsd7b, which encodes Flvcr1a, in hepatocytes (Flvcr1afl/fl;alb-cre mice). Mice were analyzed under basal conditions, after phenylhydrazine-induced hemolysis, and after induction of cytochromes P450 synthesis. Livers were collected and analyzed by histologic, quantitative real-time polymerase chain reaction, and immunoblot analyses. Hepatic P450 enzymatic activities were measured.ResultsFlvcr1afl/fl;alb-cre mice accumulated heme and iron in liver despite up-regulation of heme oxygenase 1, ferroportin, and ferritins. Hepatic heme export activity of Flvcr1a was closely associated with heme biosynthesis, which is required to sustain cytochrome induction. Upon cytochromes P450 stimulation, Flvcr1afl/fl;alb-cre mice had reduced cytochrome activity, associated with accumulation of heme in hepatocytes. The expansion of the cytosolic heme pool in these mice was likely responsible for the early inhibition of heme synthesis and increased degradation of heme, which reduced expression and activity of cytochromes P450.ConclusionsIn livers of mice, Flvcr1a maintains a free heme pool that regulates heme synthesis and degradation as well as cytochromes P450 expression and activity. These findings have important implications for drug metabolism.

Crucial Role of FLVCR1a in the Maintenance of Intestinal Heme Homeostasis

“…As FLVCR1a is reported to act as a heme exporter in erythroid cells, macrophages and hepatocytes (2,14,25,33), a similar function for this protein was expected also in intestinal cells. To address this point, the expression of the heme-induced genes HO-1, ferroportin 1 Collectively, all the data support the idea that FLVCR1a acts as a heme exporter in intestinal cells as in other cell types.…”

“…To this purpose, LoxP sites were introduced into the regions flanking Flvcr1 exon 1 to generate a floxed allele (33) ;Vil-Cre mice were viable and fertile, with normal sex ratio at birth.…”

“…The localization of heme and iron transporters in non-polarized and polarized cells and in the intestine has been carefully analysed (6,34 (33) and in Hela cells (2).…”

“…Flvcr1a mRNA is expressed ubiquitously with the highest expression observed in the liver, duodenum, kidney, lung, spleen, brain, placenta and bone marrow (15). The role of FLVCR1a as a heme exporter has been described in different cell types, including erythroid cells, macrophages and hepatocytes (2,14,25,33).…”

Regulation of heme biosynthesis and transport in metazoa

“…In macrophages of the reticuloendothelial system, FLVCR1a exports heme that is derived from ingested senescent red blood cells [72]. The heme export activity of FLVCR1a was also reported in hepatocytes and T cells [86,87]. Hypoxia induces the expression of FLVCR through HIF2 and the HIF-dependent transcription factor v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1) [88].…”