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@ARTICLE{Leibing:136954,
author = {T. Leibing and C. Géraud and I. Augustin$^*$ and M.
Boutros$^*$ and H. Augustin$^*$ and J. G. Okun and C.-D.
Langhans and J. Zierow and S. A. Wohlfeil and V. Olsavszky
and K. Schledzewski and S. Goerdt and P.-S. Koch},
title = {{A}ngiocrine {W}nt signaling controls liver growth and
metabolic maturation in mice.},
journal = {Hepatology},
volume = {68},
number = {2},
issn = {0270-9139},
address = {New York [u.a.]},
publisher = {Wiley Interscience},
reportid = {DKFZ-2018-01383},
pages = {707 - 722},
year = {2018},
note = {DKFZ-ZMBH Alliance},
abstract = {Postnatal liver development is characterized by hepatocyte
growth, proliferation, and functional maturation. Notably,
canonical Wnt signaling in hepatocytes has been identified
as an important regulator of final adult liver size and
metabolic liver zonation. The cellular origin of Wnt ligands
responsible for homeostatic liver/body weight ratio (LW/BW)
remained unclear, which was also attributable to a lack of
suitable endothelial Cre driver mice. To comprehensively
analyze the effects of hepatic angiocrine Wnt signaling on
liver development and metabolic functions, we used
endothelial subtype-specific Stab2-Cre driver mice to delete
Wls from hepatic endothelial cells (HECs). The resultant
Stab2-Cretg/wt ;Wlsfl/fl (Wls-HECKO) mice were viable, but
showed a significantly reduced LW/BW. Specifically, ablation
of angiocrine Wnt signaling impaired metabolic zonation in
the liver, as shown by loss of pericentral,
β-catenin-dependent target genes such as glutamine synthase
(Glul), RhBg, Axin2, and cytochrome P450 2E1, as well as by
extended expression of periportal genes such as arginase 1.
Furthermore, endothelial subtype-specific expression of a
c-terminally YFP-tagged Wls fusion protein in Wls-HECKO mice
(Stab2-Cretg/wt ;Wlsfl/fl ;Rosa26:Wls-YFPfl/wt [Wls-rescue])
restored metabolic liver zonation. Interestingly, lipid
metabolism was altered in Wls-HECKO mice exhibiting
significantly reduced plasma cholesterol levels, while
maintaining normal plasma triglyceride and blood glucose
concentrations. On the contrary, zonal expression of
Endomucin, LYVE1, and other markers of HEC heterogeneity
were not altered in Wls-HECKO livers.Angiocrine Wnt
signaling controls liver growth as well as development of
metabolic liver zonation in mice, whereas intrahepatic HEC
zonation is not affected. (Hepatology 2017).},
cin = {B110 / A190},
ddc = {610},
cid = {I:(DE-He78)B110-20160331 / I:(DE-He78)A190-20160331},
pnm = {321 - Basic Concepts (POF3-321)},
pid = {G:(DE-HGF)POF3-321},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29059455},
pmc = {pmc:PMC6099291},
doi = {10.1002/hep.29613},
url = {https://inrepo02.dkfz.de/record/136954},
}