Role of Nuclear Receptors in the Biliary Epithelium

Abstract

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.

Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis biliary epithelium

“…[17][18][19][20][21][22][23] NRs are differentially expressed in distinct liver cell types. 24,26 We found that primary cholangiocytes isolated from WT and CFTR-defective mice express multiple receptors, including VDR, LXR-b, FXR, and all three isoforms of PPAR, consistent with previously published data. 26 Conflicting reports have described PPARc expression in CF.…”

“…In the liver, NRs are expressed by different cellular subtypes, such as hepatocytes, stellate cells, macrophages, and cholangiocytes, with each displaying a specific expression pattern . By real‐time polymerase chain reaction (PCR) analysis, we compared the expression of different NRs in primary cholangiocytes isolated from WT and Cftr‐KO mice, cultured on Transwell inserts and grown as polarized monolayers.…”

“…[17][18][19][20][21][22][23] In the biliary epithelium, NRs participate in the regulation of many cholangiocytic functions, including protection from bile-circulating toxics (vitamin D receptor [VDR], farnesoid X receptor [FXR]), secretion (glucocorticoid receptor, FXR), and cell proliferation (hormone receptors). 24 However, it is not known if PPAR-c possesses anti-inflammatory properties in CF biliary epithelium or its potential mechanism of action.…”

A systems approach implicates nuclear receptor targeting in the Atp7b−/− mouse model of Wilson's disease

“…More broadly, suppression of FXR and GR may also inhibit biliary secretion, leading to toxic effects on liver cells and potentially influencing the development of colangiopathies 50 . Interestingly, UDP-glucornosyl transferase (UGT1A1), a key enzyme in bile acid synthesis was one of the non-nuclear proteins that were consistently identified in our analysis with less abundance in Atp7b −/− , implying attenuation of bilirubin and steroid conjugation with UDP-glucoronate and attenuation of bile secretion across the canalicular membrane 51 .…”

PPAR-alpha agonist treatment increases trefoil factor family-3 expression and attenuates apoptosis in the liver tissue of bile duct-ligated rats

“…Inflammation can be controlled by nuclear receptors such as the GR, FXR or the PPARs in various epithelial cells (30). Recently, a phosphatidylcholine (PC), 16: 0-18: 1 PC, was identified as the endogenous ligand of PPARα (31).…”