The Effect of Insulin Growth Factor on Delta-Aminolevulinic Synthase Expression

BATLLE, ALCIRA; GEREZ, ESTHER; MORA, SANDRA; PARERA, VICTORIA; OLIVERI, LEDA; ROSSETTI, MARIA VICTORIA

Burdeos

Congreso; ICPP Porphyrins and Porphyrias 2017; 2017

Acute Intermittent Porphyria (AIP) is an inherited disorder of heme biosynthesis associated to an increased expression of the hepatic isoform of delta-aminolevulinic synthase (ALAS1), the first and regulatory enzyme of the pathway, with the accumulation of the neurotoxic precursor ALA. Insulin acts on the transcription factors that regulate the mRNA levels of ALAS1. Due to the structural similarity with insulin, insulin like growth factor 1 (IGF1) can interact with insulin receptors, having insulin mimicking effects. The aim of this study was to investigate if the IGF1 has any role on ALAS1 regulation. IGF1 levels in plasma and ALA levels in urine in 50 AIP patients were determined. In the in vitro assays C3A cells were incubated in DMEM medium and treated with IGF1 for 15min at different concentrations (1, 10, 50 nM), in the presence or absence of AG1024/L, a selective inhibitor of the tyrosine fosforilation of the  subunit of IGF1 receptor. Control cells were treated with the corresponding vehicle. A high percentage of patients analysed (35%) showed values of IGF1 below the normal range and a very significant proportion (83%) of this population with low values of IGF1 showed abnormally high values of 24h-urine ALA suggesting a strong negative correlation between both parameters. In the in vitro assays, IGF1 treatment leads to a 61% reduction in the ALAS1 mRNA basal levels; this effect was reversed by the presence of AG1024/L. The strong correlation between IGF1 and ALA levels in AIP patients together with the results in vitro suggest a significant role of IGF1 on ALAS1 regulation.