Abstract
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein that is expressed on epithelial, endothelial and immune cells. CEACAM1 is a differentiation antigen involved in the maintenance of epithelial polarity that is induced during hepatocyte differentiation and liver regeneration. CEACAM1 regulates insulin sensitivity by promoting hepatic insulin clearance, and controls liver tolerance and mucosal immunity. Obese insulin-resistant humans with non-alcoholic fatty liver disease manifest loss of hepatic CEACAM1. In mice, deletion or functional inactivation of CEACAM1 impairs insulin clearance and compromises metabolic homeostasis which initiates the development of obesity and hepatic steatosis and fibrosis with other features of non-alcoholic steatohepatitis, and adipogenesis in white adipose depot. This is followed by inflammation and endothelial and cardiovascular dysfunctions. In obstructive and inflammatory liver diseases, soluble CEACAM1 is shed into human bile where it can serve as an indicator of liver disease. On immune cells, CEACAM1 acts as an immune checkpoint regulator, and deletion of Ceacam1 gene in mice causes exacerbation of inflammation and hyperactivation of myeloid cells and lymphocytes. Hence, hepatic CEACAM1 resides at the central hub of immune and metabolic homeostasis in both humans and mice. This review focuses on the regulatory role of CEACAM1 in liver and biliary tract architecture in health and disease, and on its metabolic role and function as an immune checkpoint regulator of hepatic inflammation.
Highlights
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the CEA family of highly glycosylated cellular adhesion molecules, which belongs to the immunoglobulin superfamily [1,2,3]
In our mouse model of immune-mediated hepatitis that reflects several aspects of T cell activation including cytokine response observed in autoimmune hepatitis [Concanavalin A (ConA) hepatitis, [217,218,219]], we have demonstrated that induction of intrahepatic regulatory T cells depends on IL-2 production by CEACAM1+CD4+ T cells, as IL-2 production was significantly reduced in CEACAM1−CD4+ T cells [195]
CEACAM1 can adopt dual roles in tissue differentiation, cellular proliferation, motility, and signaling that are fine-tuned by a cell- and tissue-specific relative distribution of its CEACAM1-L and CEACAM1-S isoforms
Summary
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the CEA family of highly glycosylated cellular adhesion molecules, which belongs to the immunoglobulin superfamily [1,2,3]. The expression of both major CEACAM1 isoforms (CEACAM1-S, CEACAM1-L) increases proportionally after birth, indicating that CEACAM1 is involved in hepatocyte differentiation and is a hallmark molecule inducing epithelial differentiation This hypothesis was corroborated by the description of the dynamics of CEACAM1 expression after partial hepatectomy in rats (Figure 2): CEACAM1 is initially down-regulated on the surface of hepatocytes, when cell proliferation peaks, but it is restored back to steady-state levels 15 days post-partial hepatectomy, at which point the liver is reconstituted ad integrum in healthy individuals [53,54,55]. CEACAM1 has been described as a “transformation-sensitive protein”, the loss of which is indicative of cellular transformation or de-differentiation of hepatocytes [17]
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