Cargando…

Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling

BACKGROUND & AIMS: The liver has complex interconnecting blood vessel and biliary networks; however, how the vascular and biliary network form and regulate each other and liver function are not well-understood. We aimed to examine the role of Heg in mammalian liver development and functional mai...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhu, Shichao, Rao, Xiyun, Qian, Yude, Chen, Jinbiao, Song, Renhua, Yan, Huili, Yang, Xi, Hu, Junhao, Wang, Xiaohong, Han, Zhiming, Zhu, Yi, Liu, Renjing, Jong-Leong Wong, Justin, McCaughan, Geoffrey W., Zheng, Xiangjian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059100/
https://www.ncbi.nlm.nih.gov/pubmed/35202885
http://dx.doi.org/10.1016/j.jcmgh.2022.02.010
_version_ 1784698241806237696
author Zhu, Shichao
Rao, Xiyun
Qian, Yude
Chen, Jinbiao
Song, Renhua
Yan, Huili
Yang, Xi
Hu, Junhao
Wang, Xiaohong
Han, Zhiming
Zhu, Yi
Liu, Renjing
Jong-Leong Wong, Justin
McCaughan, Geoffrey W.
Zheng, Xiangjian
author_facet Zhu, Shichao
Rao, Xiyun
Qian, Yude
Chen, Jinbiao
Song, Renhua
Yan, Huili
Yang, Xi
Hu, Junhao
Wang, Xiaohong
Han, Zhiming
Zhu, Yi
Liu, Renjing
Jong-Leong Wong, Justin
McCaughan, Geoffrey W.
Zheng, Xiangjian
author_sort Zhu, Shichao
collection PubMed
description BACKGROUND & AIMS: The liver has complex interconnecting blood vessel and biliary networks; however, how the vascular and biliary network form and regulate each other and liver function are not well-understood. We aimed to examine the role of Heg in mammalian liver development and functional maintenance. METHODS: Global (Heg(-/-)) or liver endothelial cell (EC)-specific deletion of Heg (Lyve1-Cre;Heg(fl/fl) ) mice were used to study the in vivo function of Heg in the liver. Carbon-ink anterograde and retrograde injection were used to visualize the 3-dimensional patterning of liver portal and biliary networks, respectively. RNA sequencing, histology, and molecular and biochemical assays were used to assess liver gene expression, protein distribution, liver injury response, and function. RESULTS: Heg deficiency in liver ECs led to a sparse liver vascular and biliary network. This network paucity does not compromise liver function under baseline conditions but did alter liver zonation. Molecular analysis revealed that endothelial Heg deficiency decreased expression of Wnt ligands/agonists including Wnt2, Wnt9b, and Rspo3 in ECs, which limits Axin2 mediated canonical Wnt signaling and the expression of cytochrome P450 enzymes in hepatocytes. Under chemical-induced stressed conditions, Heg-deficiency in liver ECs protected mice from drug-induced liver injuries. CONCLUSION: Our study found that endothelial Heg is essential for the 3-D patterning of the liver vascular and indirectly regulates biliary networks and proper liver zonation via its regulation of Wnt ligand production in liver endothelial cells. The endothelial Heg-initiated changes of the liver metabolic zonation and metabolic enzyme expression in hepatocytes was functionally relevant to xenobiotic metabolism and drug induced liver toxicity.
format Online
Article
Text
id pubmed-9059100
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-90591002022-05-03 Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling Zhu, Shichao Rao, Xiyun Qian, Yude Chen, Jinbiao Song, Renhua Yan, Huili Yang, Xi Hu, Junhao Wang, Xiaohong Han, Zhiming Zhu, Yi Liu, Renjing Jong-Leong Wong, Justin McCaughan, Geoffrey W. Zheng, Xiangjian Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: The liver has complex interconnecting blood vessel and biliary networks; however, how the vascular and biliary network form and regulate each other and liver function are not well-understood. We aimed to examine the role of Heg in mammalian liver development and functional maintenance. METHODS: Global (Heg(-/-)) or liver endothelial cell (EC)-specific deletion of Heg (Lyve1-Cre;Heg(fl/fl) ) mice were used to study the in vivo function of Heg in the liver. Carbon-ink anterograde and retrograde injection were used to visualize the 3-dimensional patterning of liver portal and biliary networks, respectively. RNA sequencing, histology, and molecular and biochemical assays were used to assess liver gene expression, protein distribution, liver injury response, and function. RESULTS: Heg deficiency in liver ECs led to a sparse liver vascular and biliary network. This network paucity does not compromise liver function under baseline conditions but did alter liver zonation. Molecular analysis revealed that endothelial Heg deficiency decreased expression of Wnt ligands/agonists including Wnt2, Wnt9b, and Rspo3 in ECs, which limits Axin2 mediated canonical Wnt signaling and the expression of cytochrome P450 enzymes in hepatocytes. Under chemical-induced stressed conditions, Heg-deficiency in liver ECs protected mice from drug-induced liver injuries. CONCLUSION: Our study found that endothelial Heg is essential for the 3-D patterning of the liver vascular and indirectly regulates biliary networks and proper liver zonation via its regulation of Wnt ligand production in liver endothelial cells. The endothelial Heg-initiated changes of the liver metabolic zonation and metabolic enzyme expression in hepatocytes was functionally relevant to xenobiotic metabolism and drug induced liver toxicity. Elsevier 2022-02-22 /pmc/articles/PMC9059100/ /pubmed/35202885 http://dx.doi.org/10.1016/j.jcmgh.2022.02.010 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Zhu, Shichao
Rao, Xiyun
Qian, Yude
Chen, Jinbiao
Song, Renhua
Yan, Huili
Yang, Xi
Hu, Junhao
Wang, Xiaohong
Han, Zhiming
Zhu, Yi
Liu, Renjing
Jong-Leong Wong, Justin
McCaughan, Geoffrey W.
Zheng, Xiangjian
Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling
title Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling
title_full Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling
title_fullStr Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling
title_full_unstemmed Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling
title_short Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt Signaling
title_sort liver endothelial heg regulates vascular/biliary network patterning and metabolic zonation via wnt signaling
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059100/
https://www.ncbi.nlm.nih.gov/pubmed/35202885
http://dx.doi.org/10.1016/j.jcmgh.2022.02.010
work_keys_str_mv AT zhushichao liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT raoxiyun liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT qianyude liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT chenjinbiao liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT songrenhua liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT yanhuili liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT yangxi liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT hujunhao liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT wangxiaohong liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT hanzhiming liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT zhuyi liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT liurenjing liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT jongleongwongjustin liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT mccaughangeoffreyw liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling
AT zhengxiangjian liverendothelialhegregulatesvascularbiliarynetworkpatterningandmetaboliczonationviawntsignaling