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 - Publisher Copyright:
© 2023 The Authors
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
AN - SCOPUS:85153502359
SN - 0026-0495
VL - 144
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
M1 - 155562
ER -