Resumen:
Background: PPAR alpha is a ligand-activated transcription factor that shows protective effects against metabolic disorders, inflammation and apoptosis. Primary biliary cholangitis and primary sclerosing cholangitis result in the intrahepatic accumulation of bile acids that leads to liver dysfunction and damage. Small, non-coding RNAs such as miR-155 and miR-21 are associated with silencing PPAR alpha. Methods: The expression of miR-155, miR-21 and PPAR alpha were evaluated using real-time PCR on liver tissue, as well as on human hepatocytes (HepG2) or cholangiocytes (NHCs) following exposure to lipopolysaccharide (LPS), glycodeoxycholic acid (GCDCA), lithocholic acid (LCA) and/or ursodeoxycholic acid (UDCA). Results: A reduction of PPAR alpha in primary biliary cholangitis (PBC) livers was associated with miR-21 and miR-155 upregulation. Experimental overexpression of either miR-155 or miR-21 inhibited PPAR alpha in hepatocytes, whereas, in cholangiocytes, only miR-21 suppressed PPAR alpha. Both GCDCA and LCA induced the cell type-specific upregulation of miR-155 or miR-21. In HepG2, LPS-induced miR-155 expression was blocked by a cotreatment with UDCA and was associated with PPAR alpha upregulation. In NHC cells, the expression of miR-21 was induced by LPS but did not affect PPAR alpha expression. Conclusions: Hepatic PPAR alpha expression is reduced in PBC livers as a likely result of miR-155 overexpression. UDCA effectively reduced both baseline and LPS-induced miR-155 expression, thus preventing the suppression of PPAR alpha.
