Because either a deficiency or an excess of heme is toxic to the cell, hepatic heme production has to be tightly controlled. Previous works showed that in primary cultures of adult rat hepatocytes, 20% of newly formed heme is converted to bile pigments, and 80% is used for the formation of hemoproteins, mainly CYPs.28 Our data indicate that not only heme degradation, but also FLVCR1a-mediated heme export, is critical to ensure that the amount of available heme matches cell requirements. The alteration of one of these pathways, heme synthesis, degradation or export, in
hepatocytes leads to an imbalance in heme homeostasis. In particular, FLVCR1a deletion causes an increase in the cytosolic heme fraction, click here when heme demand is increased to support CYP induction. The cytosolic heme fraction contains a pool of newly synthesized heme that serves both precursor and regulatory functions.10 The free heme pool controls heme biosynthesis, through the regulation of ALAS1. If increased, the regulatory heme pool may repress ALAS1,7
and its depletion causes ALAS1 induction.10 Our results indicate that ALAS1 induction occurs in wild-type as well as in Flvcr1a-null mice shortly after cytochrome stimulation, to sustain heme synthesis for cytochrome formation. Then, Alas1 down-regulation occurs earlier in Flvcr1a-null mice than in wild-type animals because of the negative feedback exerted by the expanded cytosolic Akt inhibitors in clinical trials free heme pool. This is in agreement with many observations,
according to which the addition of heme in hepatocyte cultures inhibits the drug-induced synthesis of ALAS. 29, 30, 31, 32 and 33 Although xenobiotics might have some primary inducing effect on hepatic ALAS1, 34 and 35 many chemical inducers are believed to increase ALAS1 by depleting the free heme pool in hepatocytes. 10 This is in agreement with our observation in wild-type mice in which ALAS1 expression, CYP activity, and microsomal heme are increased, and cytosolic heme levels are reduced after drug treatment. Conversely, liver-specific Flvcr1a-null mice showed an expansion of the cytosolic heme pool, suggesting that Flvcr1a deletion promotes intracellular heme accumulation, Glutamate dehydrogenase preventing the depletion of the free heme pool as a stimulus for ALAS1 induction and on the contrary, promoting its inhibition. In liver-specific Flvcr1a -null mice, the decreased heme synthesis well correlates with a reduction of CYP expression and activity, in line with the previous observation that the enhancement in heme synthesis is required to sustain the induction/activity of CYPs. 26, 36, 37 and 38 Conversely, when a bolus of hemin is administered to experimental animals, the induction/activity of CYPs is greatly suppressed and this effect is considered to be the result of inhibition of heme biosynthesis by ALAS1.