The spatial separation of metabolic functions along the porto-central axis within the liver lobule is termed liver zonation. The zonated metabolic endowment of hepatocytes along the sinusoid are partially influenced by adaption to changing contents of nutrients and oxygen, but is mainly regulated by the morphogenic Wnt/β-Catenin signaling pathway. How morphogens contribute to the lobular distribution of metabolic pathways is part of an evolving field in science since the last decade. For long, the pericentral located Wnt/ β-Catenin pathway was thought to be exclusively responsible for regulating metabolic tasks like ammonia and glucose metabolism. However, our group could demonstrate a dramatic impact of the morphogenic Hh pathway on lipid metabolism in the adult liver.
For a better understanding of metabolic liver zonation under morphogenic control we aimed at demonstrating the interaction and zonal distribution of Hh and Wnt/ β-Catenin signaling in the adult liver of mice.
To investigate the impact of Hh- and Wnt-signaling on liver zonation, different mouse models with a hepatocyte-specific modulation of these pathways were bred. In addition human liver material was used. To depict the porto-central distribution of several pathway markers periportal and pericentral hepatocytes were isolated using digitonin-calagenase perfusion, followed by qPCR analysis. Moreover distribution of IHC stained target proteins were quantified via the modular software tool TiQuant. Furthermore liver material was subjected for proteome analysis. Hepatocyte cell culture supernatants of our animal models were analyzed for changes in metabolite concentrations.
Our study highlights the relation between Wnt/ β-Catenin and Hh signaling in the adult liver, shows that gene expression of central Hh pathway member is periportal located, whereas Hh ligand Ihh and Wnt/ β-Catenin signaling are strongly pericentral zonated. Abundant activation of Wnt/ β-Catenin leads to a dramatic increase in Ihh, but also enhanced the expression of Hh negative regulators as Ptch2 and Sufu. The underlying matter for this spatial separation of Ihh and the remnant Hh pathway will be part of future investigations. Furthermore the outcome of proteomic approach and metabolite analysis gives an insight how these two morphogens regulate liver metabolism and contribute to a better understanding of the fine tuning mechanism on metabolic liver zonation and may help to shed light on the underlying mechanisms of deregulations like NAFLD/NASH.
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