Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

Harrison T Muturi; Hilda E Ghadieh; Raziyeh Abdolahipour; Hannah L Stankus; Getachew Debas Belew; James K Liu; Marziyeh Salehi Jahromi; Abraham D Lee; Bernhard B Singer; Isabella Angeli-Pahim; Tejasav S Sehrawat; Harmeet Malhi; Stefaan Verhulst; Leo A van Grunsven; Ali Zarrinpar; Sergio Duarte; Sonia M Najjar

doi:10.1016/j.metabol.2023.155562

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

Harrison T Muturi, Hilda E Ghadieh, Raziyeh Abdolahipour, Hannah L Stankus, Getachew Debas Belew, James K Liu, Marziyeh Salehi Jahromi, Abraham D Lee, Bernhard B Singer, Isabella Angeli-Pahim, Tejasav S Sehrawat, Harmeet Malhi, Stefaan Verhulst, Leo A van Grunsven, Ali Zarrinpar, Sergio Duarte, Sonia M Najjar

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Abstract

OBJECTIVES: Hepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1fl/fl mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1fl/fl male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target.

METHODS: VECadCre+Et1.Cc1fl/fl mice with combined endothelial loss of Cc1/Et1 genes were generated. Histological and immunohistochemical analyses were conducted on their livers and on liver tissue biopsies from adult patients undergoing bariatric surgery or from patients with NASH diagnosis receiving liver transplant.

RESULTS: Hepatic fibrosis and inflammatory infiltration developed in VECadCre+Cc1fl/fl liver parenchyma. This was preceded by increased ET1 production and reversed with combined endothelial loss of Et1. Conditioned media from VECadCre+Cc1fl/fl, but not VECadCre+Et1.Cc1fl/fl primary liver endothelial cells activated wild-type hepatic stellate cells; a process inhibited by bosentan, an ETAR/ETBR dual antagonist. Consistently, immunohistochemical analysis of liver biopsies from patients with NASH showed a decline in endothelial CEACAM1 in parallel with increased plasma endothelin1 levels and progression of hepatic fibrosis stage.

CONCLUSIONS: The data demonstrated that endothelial CEACAM1 plays a key role in preventing hepatic fibrogenesis by reducing autocrine endothelin1 production.

Original language	English
Article number	155562
Pages (from-to)	1-11
Number of pages	11
Journal	Metabolism: Clinical and Experimental
Volume	144
Early online date	21 Apr 2023
DOIs	https://doi.org/10.1016/j.metabol.2023.155562
Publication status	Published - Jul 2023

Bibliographical note

Funding Information:
This work was supported by NIH grants: R01-HL112248 , R01-DK054254 , R01-DK124126 and R01-MD012579 to S.M.N. and S.D., K08-DK113244 to AZ. H.M. is partially supported by DK111378 , S.V. by FWO 1243121N , L.A.vG. by FWO G071922N and B.B.S. by Deutsche Forschungsgemeinschaft Grant SI-1558/6-1 . S.M.N. is partially supported by Osteopathic Heritage Foundation John.J. Kopchick Eminent Research Chair.

Funding Information:
This work was supported by NIH grants: R01-HL112248, R01-DK054254, R01-DK124126 and R01-MD012579 to S.M.N. and S.D., K08-DK113244 to AZ. H.M. is partially supported by DK111378, S.V. by FWO 1243121N, L.A.vG. by FWO G071922N and B.B.S. by Deutsche Forschungsgemeinschaft Grant SI-1558/6-1. S.M.N. is partially supported by Osteopathic Heritage Foundation John.J. Kopchick Eminent Research Chair.

Publisher Copyright:
© 2023 The Authors

Copyright:
Copyright 2023 Elsevier B.V., All rights reserved.

Keywords

Endothelial cells
Endothelin1
Fibrosis
Hepatic stellate cells
Inflammation

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Muturi, H. T., Ghadieh, H. E., Abdolahipour, R., Stankus, H. L., Belew, G. D., Liu, J. K., Jahromi, M. S., Lee, A. D., Singer, B. B., Angeli-Pahim, I., Sehrawat, T. S., Malhi, H., Verhulst, S., van Grunsven, L. A., Zarrinpar, A., Duarte, S., & Najjar, S. M. (2023). Loss of CEACAM1 in endothelial cells causes hepatic fibrosis. Metabolism: Clinical and Experimental, 144, 1-11. [155562]. https://doi.org/10.1016/j.metabol.2023.155562

Muturi, Harrison T ; Ghadieh, Hilda E ; Abdolahipour, Raziyeh ; Stankus, Hannah L ; Belew, Getachew Debas ; Liu, James K ; Jahromi, Marziyeh Salehi ; Lee, Abraham D ; Singer, Bernhard B ; Angeli-Pahim, Isabella ; Sehrawat, Tejasav S ; Malhi, Harmeet ; Verhulst, Stefaan ; van Grunsven, Leo A ; Zarrinpar, Ali ; Duarte, Sergio ; Najjar, Sonia M. / Loss of CEACAM1 in endothelial cells causes hepatic fibrosis. In: Metabolism: Clinical and Experimental. 2023 ; Vol. 144. pp. 1-11.

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title = "Loss of CEACAM1 in endothelial cells causes hepatic fibrosis",

abstract = "OBJECTIVES: Hepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1fl/fl mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1fl/fl male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target.METHODS: VECadCre+Et1.Cc1fl/fl mice with combined endothelial loss of Cc1/Et1 genes were generated. Histological and immunohistochemical analyses were conducted on their livers and on liver tissue biopsies from adult patients undergoing bariatric surgery or from patients with NASH diagnosis receiving liver transplant.RESULTS: Hepatic fibrosis and inflammatory infiltration developed in VECadCre+Cc1fl/fl liver parenchyma. This was preceded by increased ET1 production and reversed with combined endothelial loss of Et1. Conditioned media from VECadCre+Cc1fl/fl, but not VECadCre+Et1.Cc1fl/fl primary liver endothelial cells activated wild-type hepatic stellate cells; a process inhibited by bosentan, an ETAR/ETBR dual antagonist. Consistently, immunohistochemical analysis of liver biopsies from patients with NASH showed a decline in endothelial CEACAM1 in parallel with increased plasma endothelin1 levels and progression of hepatic fibrosis stage.CONCLUSIONS: The data demonstrated that endothelial CEACAM1 plays a key role in preventing hepatic fibrogenesis by reducing autocrine endothelin1 production.",

keywords = "Endothelial cells, Endothelin1, Fibrosis, Hepatic stellate cells, Inflammation",

author = "Muturi, {Harrison T} and Ghadieh, {Hilda E} and Raziyeh Abdolahipour and Stankus, {Hannah L} and Belew, {Getachew Debas} and Liu, {James K} and Jahromi, {Marziyeh Salehi} and Lee, {Abraham D} and Singer, {Bernhard B} and Isabella Angeli-Pahim and Sehrawat, {Tejasav S} and Harmeet Malhi and Stefaan Verhulst and {van Grunsven}, {Leo A} and Ali Zarrinpar and Sergio Duarte and Najjar, {Sonia M}",

note = "Funding Information: This work was supported by NIH grants: R01-HL112248 , R01-DK054254 , R01-DK124126 and R01-MD012579 to S.M.N. and S.D., K08-DK113244 to AZ. H.M. is partially supported by DK111378 , S.V. by FWO 1243121N , L.A.vG. by FWO G071922N and B.B.S. by Deutsche Forschungsgemeinschaft Grant SI-1558/6-1 . S.M.N. is partially supported by Osteopathic Heritage Foundation John.J. Kopchick Eminent Research Chair. Funding Information: This work was supported by NIH grants: R01-HL112248, R01-DK054254, R01-DK124126 and R01-MD012579 to S.M.N. and S.D., K08-DK113244 to AZ. H.M. is partially supported by DK111378, S.V. by FWO 1243121N, L.A.vG. by FWO G071922N and B.B.S. by Deutsche Forschungsgemeinschaft Grant SI-1558/6-1. S.M.N. is partially supported by Osteopathic Heritage Foundation John.J. Kopchick Eminent Research Chair. Publisher Copyright: {\textcopyright} 2023 The Authors Copyright: Copyright 2023 Elsevier B.V., All rights reserved.",

year = "2023",

month = jul,

doi = "10.1016/j.metabol.2023.155562",

language = "English",

volume = "144",

pages = "1--11",

journal = "Metabolism: Clinical and Experimental",

issn = "0026-0495",

publisher = "W.B. Saunders Ltd",

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Muturi, HT, Ghadieh, HE, Abdolahipour, R, Stankus, HL, Belew, GD, Liu, JK, Jahromi, MS, Lee, AD, Singer, BB, Angeli-Pahim, I, Sehrawat, TS, Malhi, H, Verhulst, S , van Grunsven, LA, Zarrinpar, A, Duarte, S & Najjar, SM 2023, 'Loss of CEACAM1 in endothelial cells causes hepatic fibrosis', Metabolism: Clinical and Experimental, vol. 144, 155562, pp. 1-11. https://doi.org/10.1016/j.metabol.2023.155562

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis. / Muturi, Harrison T; Ghadieh, Hilda E; Abdolahipour, Raziyeh; Stankus, Hannah L; Belew, Getachew Debas; Liu, James K; Jahromi, Marziyeh Salehi; Lee, Abraham D; Singer, Bernhard B; Angeli-Pahim, Isabella; Sehrawat, Tejasav S; Malhi, Harmeet; Verhulst, Stefaan ; van Grunsven, Leo A; Zarrinpar, Ali; Duarte, Sergio; Najjar, Sonia M.

In: Metabolism: Clinical and Experimental, Vol. 144, 155562, 07.2023, p. 1-11.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

AU - Muturi, Harrison T

AU - Ghadieh, Hilda E

AU - Abdolahipour, Raziyeh

AU - Stankus, Hannah L

AU - Belew, Getachew Debas

AU - Liu, James K

AU - Jahromi, Marziyeh Salehi

AU - Lee, Abraham D

AU - Singer, Bernhard B

AU - Angeli-Pahim, Isabella

AU - Sehrawat, Tejasav S

AU - Malhi, Harmeet

AU - Verhulst, Stefaan

AU - van Grunsven, Leo A

AU - Zarrinpar, Ali

AU - Duarte, Sergio

AU - Najjar, Sonia M

N1 - Funding Information: This work was supported by NIH grants: R01-HL112248 , R01-DK054254 , R01-DK124126 and R01-MD012579 to S.M.N. and S.D., K08-DK113244 to AZ. H.M. is partially supported by DK111378 , S.V. by FWO 1243121N , L.A.vG. by FWO G071922N and B.B.S. by Deutsche Forschungsgemeinschaft Grant SI-1558/6-1 . S.M.N. is partially supported by Osteopathic Heritage Foundation John.J. Kopchick Eminent Research Chair. Funding Information: This work was supported by NIH grants: R01-HL112248, R01-DK054254, R01-DK124126 and R01-MD012579 to S.M.N. and S.D., K08-DK113244 to AZ. H.M. is partially supported by DK111378, S.V. by FWO 1243121N, L.A.vG. by FWO G071922N and B.B.S. by Deutsche Forschungsgemeinschaft Grant SI-1558/6-1. S.M.N. is partially supported by Osteopathic Heritage Foundation John.J. Kopchick Eminent Research Chair. Publisher Copyright: © 2023 The Authors Copyright: Copyright 2023 Elsevier B.V., All rights reserved.

PY - 2023/7

Y1 - 2023/7

N2 - OBJECTIVES: Hepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1fl/fl mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1fl/fl male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target.METHODS: VECadCre+Et1.Cc1fl/fl mice with combined endothelial loss of Cc1/Et1 genes were generated. Histological and immunohistochemical analyses were conducted on their livers and on liver tissue biopsies from adult patients undergoing bariatric surgery or from patients with NASH diagnosis receiving liver transplant.RESULTS: Hepatic fibrosis and inflammatory infiltration developed in VECadCre+Cc1fl/fl liver parenchyma. This was preceded by increased ET1 production and reversed with combined endothelial loss of Et1. Conditioned media from VECadCre+Cc1fl/fl, but not VECadCre+Et1.Cc1fl/fl primary liver endothelial cells activated wild-type hepatic stellate cells; a process inhibited by bosentan, an ETAR/ETBR dual antagonist. Consistently, immunohistochemical analysis of liver biopsies from patients with NASH showed a decline in endothelial CEACAM1 in parallel with increased plasma endothelin1 levels and progression of hepatic fibrosis stage.CONCLUSIONS: The data demonstrated that endothelial CEACAM1 plays a key role in preventing hepatic fibrogenesis by reducing autocrine endothelin1 production.

AB - OBJECTIVES: Hepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1fl/fl mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1fl/fl male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target.METHODS: VECadCre+Et1.Cc1fl/fl mice with combined endothelial loss of Cc1/Et1 genes were generated. Histological and immunohistochemical analyses were conducted on their livers and on liver tissue biopsies from adult patients undergoing bariatric surgery or from patients with NASH diagnosis receiving liver transplant.RESULTS: Hepatic fibrosis and inflammatory infiltration developed in VECadCre+Cc1fl/fl liver parenchyma. This was preceded by increased ET1 production and reversed with combined endothelial loss of Et1. Conditioned media from VECadCre+Cc1fl/fl, but not VECadCre+Et1.Cc1fl/fl primary liver endothelial cells activated wild-type hepatic stellate cells; a process inhibited by bosentan, an ETAR/ETBR dual antagonist. Consistently, immunohistochemical analysis of liver biopsies from patients with NASH showed a decline in endothelial CEACAM1 in parallel with increased plasma endothelin1 levels and progression of hepatic fibrosis stage.CONCLUSIONS: The data demonstrated that endothelial CEACAM1 plays a key role in preventing hepatic fibrogenesis by reducing autocrine endothelin1 production.

KW - Endothelial cells

KW - Endothelin1

KW - Fibrosis

KW - Hepatic stellate cells

KW - Inflammation

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U2 - 10.1016/j.metabol.2023.155562

DO - 10.1016/j.metabol.2023.155562

M3 - Article

C2 - 37088122

VL - 144

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JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

SN - 0026-0495

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ER -

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

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