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Review
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The Roles of Notch Signaling in Liver Development and Disease

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Review

The Roles of Notch Signaling in Liver Development and Disease

Joshua M Adams et al. Biomolecules.

Abstract

The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch activity in proper liver development and function. Specifically, we discuss the latest discoveries on how Notch, in conjunction with other signaling pathways, aids in proper liver development, regeneration and repair. In addition, we review the latest in the role of Notch signaling in the pathogenesis of liver fibrosis and chronic liver disease. Finally, recent evidence has shed light on the emerging connection between Notch signaling and glucose and lipid metabolism. We hope that highlighting the major advances in the roles of Notch signaling in the liver will stimulate further research in this exciting field and generate additional ideas for therapeutic manipulation of the Notch pathway in liver diseases.

Keywords: Alagille syndrome; biliary development; genetic modifiers; liver; liver fibrosis; liver metabolism; liver regeneration; notch signaling.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study, in the writing of the manuscript or in the decision to publish the manuscript.

Figures

Figure 1
Figure 1
Notch signaling promotes biliary morphogenesis and the extension of the biliary tree. (A) A representation of cholangiocyte specification and biliary morphogenesis from E12.5 to the early postnatal period. (B) A three-dimensional (3D) representation of biliary development based on [17]. Differentiated cholangiocytes are first incorporated in a continuous homogeneous luminal network. This network is later reorganized into hierarchical tubular structures that form the adult biliary tree.
Figure 2
Figure 2
TGFβ promotes hepatocyte to cholangiocyte transdifferentiation in livers with severe Notch deficiency. (A) In a Notch-sufficient context, Notch and transforming growth factor beta (TGFβ) signaling help in specifying cholangiocytes and promoting the development of mature biliary structures. Wingless-type MMTV integration site (WNT), Hippo and bone morphogenetic protein (BMP) signaling promote hepatocyte fate. (B) In a severe Notch-deficient context, biliary morphogenesis is impaired and TGFβ signaling promotes transdifferentiation of hepatocytes to cholangiocytes (the orange arrow) to form patent biliary structures [35].
Figure 3
Figure 3
Notch signaling promotes Hepatic Stellate Cell (HSC) differentiation into myofibroblasts and liver fibrosis: (A) when Notch signaling is low, liver sinusoidal endothelial cells (LSECs) secrete nitric oxide, which inhibits the differentiation of hepatic stellate cells (HSCs) into myofibroblasts (MyoF). (B) Increased Notch activity in LSECs promotes their basement membrane (BM) production and reduces their fenestration and nitric oxide secretion, which in turn relieves nitric oxide’s inhibitory effect on HSC-to-myofibroblast differentiation. Additionally, increased Notch signaling in HSCs directly promotes their differentiation into myofibroblasts. Finally, activation of Notch signaling in hepatocytes promotes the secretion of SPP1 (OPN) by these cells, which also promotes myofibroblast differentiation. Myofibroblasts generated in response to increased Notch signaling promote liver fibrosis.

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