Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases

Abstract

The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction.

Figure 1

Schematic drawing of the growth factors, gastrointestinal hormones, and neuropeptides/neuromodulators that affect cholangiocyte proliferation with decreases or increases with biliary mass.

Figure 2

Illustration of the neuroendocrine factors secreted by cholangiocytes that regulate their proliferation and secretory function and their known and postulated interactions with various cell types in the portal track microenvironment. IL-6, interleukin-6.