Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt SignalingSummary
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X22000376 |
| _version_ | 1818206890190962688 |
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| author | Shichao Zhu Xiyun Rao Yude Qian Jinbiao Chen Renhua Song Huili Yan Xi Yang Junhao Hu Xiaohong Wang Zhiming Han Yi Zhu Renjing Liu Justin Jong-Leong Wong Geoffrey W. McCaughan Xiangjian Zheng |
| author_facet | Shichao Zhu Xiyun Rao Yude Qian Jinbiao Chen Renhua Song Huili Yan Xi Yang Junhao Hu Xiaohong Wang Zhiming Han Yi Zhu Renjing Liu Justin Jong-Leong Wong Geoffrey W. McCaughan Xiangjian Zheng |
| author_sort | Shichao Zhu |
| collection | DOAJ |
| 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;Hegfl/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. |
| first_indexed | 2024-12-12T04:20:13Z |
| format | Article |
| id | doaj.art-9c9ef969c97c4420b30290118e1793e1 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-12T04:20:13Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-9c9ef969c97c4420b30290118e1793e12022-12-22T00:38:20ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-0113617571783Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt SignalingSummaryShichao Zhu0Xiyun Rao1Yude Qian2Jinbiao Chen3Renhua Song4Huili Yan5Xi Yang6Junhao Hu7Xiaohong Wang8Zhiming Han9Yi Zhu10Renjing Liu11Justin Jong-Leong Wong12Geoffrey W. McCaughan13Xiangjian Zheng14Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaDepartment of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaDepartment of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaLiver Injury and Cancer Program Centenary Institute and Sydney Medical School, The University of Sydney, A.W Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaEpigenetics and RNA Biology Program Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, NSW, AustraliaDepartment of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaDepartment of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, ChinaVascular Epigenetics Laboratory, Victor Chang Cardiac Research Institute, Sydney, NSW, AustraliaEpigenetics and RNA Biology Program Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, NSW, AustraliaLiver Injury and Cancer Program Centenary Institute and Sydney Medical School, The University of Sydney, A.W Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaDepartment of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Correspondence Address correspondence to: Dr Xiangjian Zheng, Pharmacology, Tianjin Medical University, No 22 Qi Xiang Tai Rd, Tianjin 300070, China. tel: 86-22-8333-6835.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;Hegfl/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.http://www.sciencedirect.com/science/article/pii/S2352345X22000376HegLiver injuryLiver ZonationWnt |
| spellingShingle | Shichao Zhu Xiyun Rao Yude Qian Jinbiao Chen Renhua Song Huili Yan Xi Yang Junhao Hu Xiaohong Wang Zhiming Han Yi Zhu Renjing Liu Justin Jong-Leong Wong Geoffrey W. McCaughan Xiangjian Zheng Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt SignalingSummary Cellular and Molecular Gastroenterology and Hepatology Heg Liver injury Liver Zonation Wnt |
| title | Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt SignalingSummary |
| title_full | Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt SignalingSummary |
| title_fullStr | Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt SignalingSummary |
| title_full_unstemmed | Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt SignalingSummary |
| title_short | Liver Endothelial Heg Regulates Vascular/Biliary Network Patterning and Metabolic Zonation Via Wnt SignalingSummary |
| title_sort | liver endothelial heg regulates vascular biliary network patterning and metabolic zonation via wnt signalingsummary |
| topic | Heg Liver injury Liver Zonation Wnt |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X22000376 |
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