Wnt/␤-catenin signaling has been found to play key roles in metabolic zonation of adult liver, regeneration, and hepatocellular carcinogenesis. In this review, recent progress in this field is summarized, in particular the rapidly growing knowledge about the various interactions of ␤-catenin with many transcription factors involved in controlling metabolism. These interactions may provide the basis for understanding how the wide range of activities of Wnt/␤-catenin signaling is differentially interpreted. Based on these results, a three-level mode for the molecular interpretation of ␤-catenin activity gradients in liver is proposed favoring cell differentiation, metabolic zonation, and proliferation. While derangement of the combinatorial interplay of the various transcription factors with ␤-catenin at the intermediary activity level may contribute to the development of metabolic diseases, extremely high activation of ␤-catenin may eventually lead to initiation and progression of hepatocellular tumors. Developmental Dynamics 239:45-55, 2010.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and is increasing in prevalence. The pathomechanisms, however, are poorly understood. This study assessed the unexpected role of the Hedgehog pathway in adult liver lipid metabolism. Using transgenic mice with conditional hepatocyte-specific deletion of Smoothened in adult mice, we showed that hepatocellular inhibition of Hedgehog signaling leads to steatosis by altering the abundance of the transcription factors GLI1 and GLI3. This steatotic 'Gli-code' caused the modulation of a complex network of lipogenic transcription factors and enzymes, including SREBP1 and PNPLA3, as demonstrated by microarray analysis and siRNA experiments and could be confirmed in other steatotic mouse models as well as in steatotic human livers. Conversely, activation of the Hedgehog pathway reversed the "Gli-code" and mitigated hepatic steatosis. Collectively, our results reveal that dysfunctions in the Hedgehog pathway play an important role in hepatic steatosis and beyond.DOI: http://dx.doi.org/10.7554/eLife.13308.001

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In 1963, Binns et al. [1] described the development of congenital cyclopean-type malformations in lambs following maternal ingestion of the range plant Veratrum californicum (Durand). While cattle, sheep, rat, and rabbit embryos under such conditions develop mainly cyclopia, chicken embryos preferentially develop holoprosencephaly [1-4]. Holoprosencephaly is a developmental field defect of impaired midline cleavage of the embryonic forebrain (for reviews, see [5] and [6]). However, there is a wide phenotypic spectrum depending upon the specific cause of this malformation. In its most extreme form, it is associated with cyclopia, which is characterized by one eye being located centrally over the root of the nose (l " Fig. 1). In sheep such effects occur when pregnant ewes are exposed on day 14 of gestation. The most frequent defects caused by exposure at later periods of gestation, around day 30, are limb deformities, palate defects, and severe tracheal stenosis [7]. All these defects in