Heme exporter FLVCR1a regulates heme synthesis and degradation and controls activity of cytochromes P450.
OBJECTIVE
The 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.


METHODS
We created mice with conditional disruption of Mfsd7b, which encodes Flvcr1a, in hepatocytes (Flvcr1a(fl/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.


RESULTS
Flvcr1a(fl/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, Flvcr1a(fl/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.


CONCLUSIONS
In 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.
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Francesca
F
Vinchi
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Giada
G
Ingoglia
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Deborah
D
Chiabrando
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Sonia
S
Mercurio
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Emilia
E
Turco
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Lorenzo
L
Silengo
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Fiorella
F
Altruda
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Electronic address: emanuela.tolosano@unito.it.
Emanuela
E
Tolosano
D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D005293:Ferritins / Q000378:metabolism; D006418:Heme / Q000096:biosynthesis / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006461:Hemolysis; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006706:Homeostasis; D007093:Imidazoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010659:Phenylhydrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D000098742:Ferroportin
D027682:Cation Transport Proteins; C526650:Flvcr1 protein, mouse; D007093:Imidazoles; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D010659:Phenylhydrazines; D012333:RNA, Messenger; D011991:Receptors, Virus; D000098742:Ferroportin; C030299:phenylhydrazine; D001564:Benzo(a)pyrene; D006418:Heme; C029899:imidazole; D003907:Dexamethasone; D005293:Ferritins; D003577:Cytochrome P-450 Enzyme System; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
ALAS1; CYP; Flvcr; Flvcr1; HO-1