MODULATION OF LDL RECEPTOR MESSENGER-RNA STABILITY BY PHORBOL ESTERS IN HUMAN LIVER-CELL CULTURE MODELS

In the human hepatocarcinoma cell lines HepG2 and Hep3B, low density l ipoprotein receptor (LDLR) mRNA levels were rapidly and transiently in duced after treatment with phorbol-12-myristate-13-acetate (PMA), incr easing by approximately 50-fold and 8-fold, respectively, within 4 h b efore returning to near basal levels by 24 h. The difference in magnit ude of mRNA accumulation between these cell lines is at least partly d ue to a rapid 2- to 2.5-fold stabilization of LDLR mRNA in HepG2 cells after PMA treatment. Stabilization of LDLR mRNA in response to PMA wa s also observed in HH01 cells, a human hepatocyte coculture system der ived from normal human liver. In both HepG2 and HH01 cells, PMA treatm ent induced a rapid morphological change with characteristics of cytos keletal reorganization. The changes in morphology and stabilization of LDLR mRNA by PMA were coincident in the cell lines tested and were in dependent of de novo gene expression. Subcellular fractionation studie s indicated that LDLR polysomes may be associated with the cytoskeleto n in HepG2 cells. Disruption of the actin cytoskeleton but not microtu bules abrogated stabilization of LDLR mRNA by PMA. These data suggest that components of the actin cytoskeleton are involved in the regulate d decay of LDLR mRNA in some human liver cell culture systems.