ABSTRACT: Heme is an essential prosthetic group of proteins involved in oxygen transport, energy metabolism and nitric oxide production. ALAS1 (5-aminolevulinate synthase) is the rate-limiting enzyme in heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target for the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). In primary human hepatocytes and in HepG2 cells, PPARα agonists induced an increase in ALAS1 mRNA levels, which was abolished by PPARα silencing. These effects are mediated by two functional PPAR binding sites at positions − 9 and − 2.3 kb relative to the ALAS1 transcription start site. PPARα ligand treatment also up-regulated the mRNA levels of the genes ALAD (5-aminolevulinate dehydratase), UROS (uroporphyrinogen III synthase), UROD (uroporphyrinogen decarboxylase), CPOX (coproporphyrinogen oxidase) and PPOX (protoporphyrinogen oxidase) encoding for enzymes controlling further steps in heme biosynthesis. In HepG2 cells treated with PPARα agonists and in mouse liver upon fasting, the association of PPARα, its partner retinoid X receptor, PPARγ co-activator 1α and activated RNA polymerase II with the transcription start site region of all six genes was increased, leading to higher levels of the metabolite heme. In conclusion, these data strongly support a role of PPARα in the regulation of human ALAS1 and of five additional genes of the pathway, consequently leading to increased heme synthesis.
Journal of Molecular Biology 388 (2010) 2.