The hedgehog signaling pathway is a key regulator in embryonic development. The pathway includes the intercellular signaling molecule “Hedgehog” (Hh) that was first identified in Drosophila, where Hh is involved in establishing the basis of the fly body plan. In mammals three Hedgehog homologues exist, Sonic hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog (Dhh). Shh signaling is the best studied mechanism and is crucial during vertebrate embryonic development. Shh is known to bind on the Patched-1 (Ptch1) receptor on its target cell. In the absence of Shh, Ptch1 inhibits the protein Smoothened (Smo) by transporting a small molecule inhibitor of Smo, probably vitamin D or a related precursor. When Smo is inhibited, two members of the transcription factors of the GLI family, namely GLI2 and GLI3 are truncated to their repressor forms, while GLI1 is completely degraded. The truncation of GLI2 and GLI3 is initiated by a complex of proteins including Supressor of fused (SuFu). Upon Shh binding, the transport activity of Ptch1 is switched from the Smo inhibitor to oxysterols, thereby allowing oxysterols to accumulate around Smo. Thus, Smo is activated leading to an activation cascade for all three members of the GLI family which then exist in their untruncated, activating form. The activated GLI molecules accumulate in the nucleus and control transcription of hedgehog target genes.
Disrupted hedgehog signaling in embryonic development leads to severe developmental abnormalities, particularly in the brain, skeleton, musculature, gastrointestinal tract and lungs. Strongly activated hedgehog signaling has been described in cancers of various organs, like brain, lung, mammary gland, prostate and skin.
Several activators of Hh signaling have been described. Brunton 2009 discloses Hh-agonists according to following formula (1)

Apart from being involved in embryonic development and cancer development it is suggested that Hh signaling in different cells is involved in the development of a variety of diseases. It is described that Hh signaling regulates epithelial-mesenchymal transition in cholangiocytes of the adult bile duct during biliary fibrosis (Omenetti 2009, Greenbaum 2008). Further, activation of Hh signaling has been described to be therapeutically useful in the treatment of depression (US2006078499A1). Activators of Hh signalling were described for therapeutic application to epithelial tissues. Here, treatment of tissue disorders as well as surgical or cosmetic applications of tissues like skin, cornea, lens and other ocular tissue, mucosal membranes and periodontal epithelium should be mentioned (U.S. Pat. No. 7,115,653, WO 0174344 A2, EP 1671634 A1).
The role of hedgehog signaling in liver cells recently got into focus of research. Sicklick 2005 and Sicklick 2006 proposed that Hh signaling is required for the activation of hepatic stellate cells (HSC) and that Hh signaling is relevant for the survival of hepatic precursor cells (HPC). The review article by Omenetti 2008 summarizes the role of Hh signaling during liver development, inflammation and cancer. According to Omenetti 2008, the role of Hh signaling in liver development is not fully understood, whereas in the adult liver the expression of Hh ligands as well as a responsiveness to Hh ligands was observed in HSC and liver epithelial progenitors. Constitutive activation of Hh signalling has been observed in both hepatocellular carcinoma and cholangiocarcinoma. According to Omenetti 2008, it is believed that mature hepatocytes are not Hh-responsive.
The role of Hh signalling in non-alcoholic fatty liver disease (NAFLD) was examined in several studies. Syn 2009 studied Hh signaling in the pathogenesis of NAFLD, non-alcoholic steatohepatitis (NASH) and cirrhosis of the liver. Syn 2009 observed low expression of Shh and GLI2 in NAFLD-patients and increased expression thereof in NASH and cirrhosis. In summary, it is suggested that activation of Hh signaling in HPC is associated with disease pathogenicity.
Trappoliere 2005 give an overview on strategies for treatment of fatty liver diseases. Current methods of treatment include                treating the underlying cause or predisposition (weight, metabolism disorders, diabetes),        modulation of cytokine levels involved in the disease,        inhibition of lipid peroxidation and progression of fibrosis (e. g. by administration of antioxidants or antifibrotic substances).        
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