As the biggest metabolic organ the liver possesses a variety of functions, including carbohydrate and lipid metabolism. The smallest functional unit thereby is displayed by the liver lobules showing a metabolic zonation. Hepatocytes can be roughly divided in periportal (PP) and pericentral (PC) cells. Numerous genes and enzymes are involved in the regulation processes of the metabolism; especially nuclear receptors like Ppars possess a coordinating role for many physiological functions. While Pparα promotes fatty acid oxidation and, thus, is controlling lipid catabolism, Pparγ promotes the storage of lipids. Transcription factors like Ppars also interact with morphogenic pathways. One example is the hedgehog (HH) signaling pathway, which is crucial for embryogenesis and organogenesis. Recent investigations showed that this pathway also plays a critical role in adult organs such as the liver but molecular mechanisms are not well characterized. Our aim was to investigate the interactions between Ppars and Gli-transcrictiption factors (TF). C57Bl6/N mice (12 week, ♂, 20-25 g) were used to and maintained under controlled conditions (const. 12:12h LD cycle). Mice were anaesthetized with a mixture of atropine (0.1mg/kg), ketamine (100mg/kg) and rompune (5mg/kg). To examine hepatic gene expression, RNA was extracted from whole liver lysates or hepatocytes which were isolated by using collagenase perfusion technique. To receive PP and PC hepatocytes a digitonin-collagenase perfusion was performed. To investigate the functions of Pparα/γ as well as of Gli1/2/3, siRNA-mediated in vitro knockdown (KD) of those genes was performed. Alterations in gene expression of HH signaling components and lipid metabolism target genes were determined by using micro-arrays and qRT-PCR. Values are means ± S.E.M. normalized to β-actin as housekeeping gene, compared by MWUtest. mRNA expression profiles showed a heterogeneously distribution of Pparα/γ. Pparγ is localized pericentral (PC:1±0.26 vs PP:0.17±0.12,p<0.05; n=3-4), whereas for Pparα no preferential zonated localization could be determined. Transcriptome analyses revealed that a wide variety of genes like genes for biological processes (e.g. ion transports, cell cycle) are effected by Pparγ-KD (n=3). Pparγ-KD also results in downregulation of all 3 Gli-TFs (e.g. Gli1: 0.55±0.13,p<0.05; Gli2:0.42±0.14,p<0.01; Gli3:0.05±0.03,p<0.05; n=7-8). Gli1/2/3-KD showed effects on Ppar-gene expression. Both Ppar heterologous are significantly upregulated in response to Gli3-KD (Pparα: 2.62±0.61, p<0.05; Pparγ: 1.66±0.31, p<0.05; n=4-6). KD-experiments of Ppars and Gli-TFs and their related mRNA expression profiles indicate a putative mutual interaction between these nuclear receptors and HH signaling forming a negative feedback loop. Future experiments should investigate molecular details of this interaction.