Ursodeoxycholic acid influences the expression of p27kip1 but not FoxO1 in patients with non-cirrhotic primary biliary cirrhosis

Abstract

BACKGROUND: Enhanced expression of cell cycle inhibitor p27(kip1) suppresses cell proliferation. Ursodeoxycholic acid (UDCA) delays progression of primary biliary cirrhosis (PBC) but its effect on p27(kip1) expression is uncertain. AIMS: To analyze the expression of p27(kip1) and its transcription modulator FoxO1 in patients with PBC, and to assess the impact of UDCA on this pathway. MATERIALS AND METHODS: The examined human tissue included explanted livers from patients with cirrhotic PBC (n = 23), primary sclerosing cholangitis (PSC; n = 9), alcoholic liver disease (ALD; n = 9), and routine liver biopsies from patients with non-cirrhotic PBC (n = 26). Healthy liver samples served as controls (n = 19). Livers of FoxO-deficient mice were also studied. mRNA and protein expressions were analyzed by real-time PCR and Western blot. RESULTS: p27(kip1) expression was increased in cirrhotic and non-cirrhotic PBC. FoxO1 mRNA levels were increased in PBC (8.5-fold increase versus controls). FoxO1 protein expression in PBC was comparable to controls, but it was decreased in patients with PSC and ALD (63% and 70% reduction, respectively; both P < 0.05 versus control). UDCA-treated non-cirrhotic patients with PBC showed decreased expression of p27(kip1) mRNA. CONCLUSION: PBC progression is characterized by a FoxO1-independent increase of p27(kip1) expression. In early PBC, UDCA may enhance liver regeneration via p27(kip1)-dependent mechanism.