The Cl HCO anion exchanger AE is found on
The Cl−/HCO3− anion exchanger 2 (AE2) is found on cholangiocytes and regulates intracellular pH homeostasis and stimulates bicarbonate secretion. Previous reports have revealed that PBC patients show decreased biliary AE2 expression, and researchers hypothesized that this decrease in AE2 dna synthesis may be regulated by miRNA expression. According to miRBase database analysis, miR-506 was predicted to potentially target the 3′ UTR of human AE2 mRNA, and miR-506 was also found to be highly upregulated in human PBC liver samples compared with healthy controls by microarray.In situ hybridization verified that the increased miR-506 hepatic expression noted in human PBC was largely seen in cholangiocytes compared with other liver cell types. To confirm the activity of miR-506 on AE2, miR-506 was overexpressed in normal human cholangiocytes and decreased AE2 expression and activity were observed. The ability of miR-506 to target AE2 was validated in vitro using luciferase assay and site-directed mutagenesis in the 3′ UTR of AE2. To analyze miR-506 and AE2 expression in human PBC, the authors used primary cultures of isolated human PBC cholangiocytes obtained from a liver explant from a transplanted female patient. From this primary cell line, the authors found that the cultured human PBC cholangiocytes showed increased miR-506 expression, accompanied with decreased AE2 expression and activity, and transfection of the human PBC cholangiocytes with anti-miR-506 restored AE2 activity. Overall, this paper indicates hepatic levels of miR-506 as a diagnostic tool. Considering AE2 is a key player in biliary function, and decreased AE2 activity is noted in PBC patients, targeting miR-506 may provide a much-needed therapeutic target for patients with PBC.
Biliary atresia Biliary atresia (BA) is a neonatal liver disease that is characterized by inflammation and obliteration of the biliary tree leading to cholestasis and hepatic fibrosis. If untreated, this damage can cause progressive conjugated hyperbilirubinemia, cirrhosis and hepatic failure. The incidence of BA is approximately one in 10,000 births worldwide, but without therapeutic intervention, BA can be fatal within 2 years, with a median survival rate of eight months. Considering the rarity of the disease, it is imperative that proper diagnostic tools are developed. Curative treatments have yet to be established for BA. The Kasai procedure is primarily performed to help restore bile flow and hopefully manage symptoms of the disease. One-third of patients who undergo the Kasai procedure will survive more than 10 years without liver transplantation, while another third will have proper bile drainage but require liver transplantation prior to age 10 due to complications with cirrhosis; the last third of patients will have an inadequate response to the surgery and further develop progressive fibrosis and cirrhosis. A recent study analyzed the efficacy of circulating miRNAs as markers of disease severity and etiology in pediatrics with cholestatic liver disease. Analysis of serum levels revealed that BA patients, as well as pediatrics with other cholestatic liver diseases, had increased levels of miR-21 compared with healthy controls. Notably, BA patients had increased levels of miR-21 compared to pediatrics with other cholestatic liver diseases, indicating miR-21 as a possible BA-specific marker to rule out other pediatric cholestatic diseases. However, circulating miR-21 levels did not correlate with the degree of BA-associated hepatic fibrosis. These results suggest that circulating miR-21 levels may serve as a useful diagnostic marker to identify BA from other pediatric cholestatic diseases, but it may not be suitable to determining the severity of BA-associated liver fibrosis. These findings were supported by another publication that found that hepatic expression of miR-21 was upregulated in BA patients compared with healthy controls.