Role of nuclear receptors in the biliary epithelium

The biliary epithelium is organized as a single layer of biliary epithelial cells lining the biliary tree. Biliary epithelial cells have three major biological functions: protection, secretion and proliferation. These functions are all controlled by nuclear receptors. The biliary tree conveys bile, a complex fluid containing toxics such as endotoxins, from the liver to the duodenum. Active protection against endotoxins can be elicited by the vitamin D receptor or the farnesoid X receptor (FXR), thus avoiding constant inflammation of the biliary epithelium. Anti-inflammatory activities may be triggered by PPAR-α and -γ, which are also able to inhibit the deleterious effect of bacterial products. Secretion, a major function of biliary epithelial cells, is mainly regulated by circulating factors. Luminal factors, such as bile salts, may also control fluid secretion by classical intracellular pathways, membrane receptors or nuclear receptors. FXR or the glucocorticoid receptor have indeed been shown to increase the expression of genes encoding membrane-bound proteins that participate in biliary epithelial cell secretion. Biliary epithelial cells are quiescent cells that are able to proliferate in pathophysiological settings. Inhibition of estrogen receptor signaling decreases pathological biliary epithelial cell proliferation. Furthermore, progesterone, through the progesterone receptor, increases biliary epithelial cells proliferation. Taken together these observations suggest that nuclear receptors are involved in the control of biliary epithelial cell biology. A better delineation of the specific biliary epithelial cell functions controlled by nuclear receptors may shed light on potential therapeutic molecular targets of cholangiopathies.