Abstract

Background. Enhanced expression of cell cycle inhibitor p27kip1 suppresses cell proliferation. Ursodeoxycholic acid (UDCA) delays progression of primary biliary cirrhosis (PBC) but its effect on p27kip1 expression is uncertain. Aims. To analyze the expression of p27kip1 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. p27kip1 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 p27kip1 mRNA. Conclusion. PBC progression is characterized by a FoxO1-independent increase of p27kip1 expression. In early PBC, UDCA may enhance liver regeneration via p27kip1-dependent mechanism.

Highlights

  • Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by an autoimmune-mediated inflammatory destruction of biliary epithelial cells [1,2,3,4] of the small intrahepatic small bile ducts

  • We demonstrated an enhanced expression of p27kip1 mRNA in non-cirrhotic and cirrhotic primary biliary cirrhosis (PBC) livers and noted that the level of p27kip1 transcript was much higher in cirrhotic versus non-cirrhotic patients with PBC

  • The FoxO1 mRNA expression was significantly increased in cirrhotic PBC

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Summary

Introduction

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by an autoimmune-mediated inflammatory destruction of biliary epithelial cells [1,2,3,4] of the small intrahepatic small bile ducts. Recent data have convincingly demonstrated that the cell cycle regulator p27kip contributes to the inhibition of proliferative activity of differentiated hepatocytes. Ursodeoxycholic acid (UDCA) delays progression of primary biliary cirrhosis (PBC) but its effect on p27kip expression is uncertain. To analyze the expression of p27kip and its transcription modulator FoxO1 in patients with PBC, and to assess the impact of UDCA on this pathway. 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 p27kip mRNA. PBC progression is characterized by a FoxO1-independent increase of p27kip expression. In early PBC, UDCA may enhance liver regeneration via p27kip1-dependent mechanism

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