UP-REGULATION OF THE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEINBY DEXAMETHASONE IN HEPG2 CELLS

Dexamethasone has been shown to decrease the expression of the low den sity lipoprotein (LDL) receptor, but its effect on other members of th e LDL receptor family is not known. We studied the effect of dexametha sone in HepG2 cells on the expression of the LDL receptor family membe rs using radiolabeled receptor associated protein (RAP) which binds to all the members of the family. Treatment of HepG2 cells with increasi ng concentrations of dexamethasone resulted in a 2-fold increase in th e binding and degradation of RAP. To identify the receptor responsible for the increased binding and degradation of RAP, we used specific li gands. For LDL receptor, we used LDL itself. For the LDL receptor-rela ted protein/alpha(2)-macroglobulin receptor, we used activated alpha(2 )-macroglobulin. The binding of LDL to HepG2 cells was decreased, wher eas binding and degradation of activated alpha(2)-macroglobulin was in creased by 2-fold suggesting that dexamethasone increased LRP expressi on. Increased LRP expression was positively correlated with the increa se in the steady-state levels and transcript numbers of the LRP mRNA; no changes in RAP or Gamma-actin mRNA levels were observed. Increased mRNA levels were not due to an increased rate of transcription of the gene as assessed by nuclear run-on experiments. These studies indicate that dexamethasone increases cell-surface LRP activity in HepG2 cells by increasing the steady state mRNA levels and suggest that post-tran scriptional mechanisms play a role in controlling LRP mRNA levels.