DEXAMETHASONE AND INSULIN DEMONSTRATE MARKED AND OPPOSITE REGULATION OF THE STEADY-STATE MESSENGER-RNA LEVEL OF THE PEROXISOMAL PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) IN HEPATIC CELLS - HORMONAL MODULATION OF FATTY-ACID-INDUCED TRANSCRIPTION

Fatty acids and the peroxisomal proliferator, 3-tetradecylthioacetic a cid (TTA) stimulate transcription of peroxisomal beta-oxidation enzyme s. Recently, we have shown that their actions are markedly modulated b y dexamethasone and insulin which show synergistic and inhibitory effe cts, respectively. In this study, we describe the regulation of the pe roxisomal proliferator-activated receptor (PPAR), a member of the ster oid-hormone-receptor superfamily, in a similar manner by hormones and fatty acids, supporting the hypothesis that PPAR may act as a ligand-a ctivated transcription factor. Northern-blot analysis of steady-state mRNA levels revealed three different specific transcripts for PPAR of 10.2, 4.6 and 1.8 kb, and the former two being regulated in hepatic ti ssue, hepatocytes and hepatoma cells. Dexamethasone produced a pronoun ced overall stimulatory effect (15.3-fold) in rat hepatocytes, while i nsulin blocked this action completely. Minor inductions of PPAR mRNA ( up to twofold induction) were observed when different fatty acids were administrated alone. However, in combination with dexamethasone, addi tive or synergistic actions, mounting to 24-fold stimulation, were obs erved, while insulin always exerted an over-riding down-regulatory eff ect. In non-fasting rats receiving dexamethasone, elevation of serum i nsulin, a slight increase in serum free fatty acids accompanied by PPA R mRNA level increases of 2.4-fold and stimulation of liver peroxisoma l acyl-CoA oxidase mRNA were observed. Our results suggest that PPAR m RNA expression is under strict hormonal control and that the fatty aci ds and hormones affect PPAR mRNA levels in a manner analogous to the r egulation of the peroxisomal beta-oxidation enzymes. The PPAR gene-reg ulating unit apparently contains hormone-response elements (HRE) for d examethasone and insulin, which are thus functionally important for PP AR transcription in liver cells, making a significant enhancement or i nhibition of the physiological actions of fatty acids possible.