Dexamethasone and Insulin Demonstrate Marked and Opposite Regulation of the Steady‐State mRNA Level of the Peroxisomal Proliferator‐Activated Receptor (PPAR) in Hepatic Cells: Hormonal Modulation of Fatty‐Acid‐Induced Transcription

Abstract

Fatty acids and the peroxisomal proliferator, 3‐tetradecylthioacetic acid (TTA) stimulate transcription of peroxisomal β‐oxidation enzymes. Recently, we have shown that their actions are markedly modulated by dexamethasone and insulin which show synergistic and inhibitory effects, respectively. In this study, we describe the regulation of the peroxisomal proliferator‐activated receptor (PPAR), a member of the steroid‐hormone‐receptor superfamily, in a similar manner by hormones and fatty acids, supporting the hypothesis that PPAR may act as a ligand‐activated 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 tissue, hepatocytes and hepatoma cells. Dexamethasone produced a pronounced overall stimulatory effect (15.3‐fold) in rat hepatocytes, while insulin 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, additive or synergistic actions, mounting to 24‐fold stimulation, were observed, while insulin always exerted an over‐riding down‐regulatory effect. In non‐fasting rats receiving dexamethasone, elevation of serum insulin, a slight increase in serum free fatty acids accompanied by PPAR mRNA level increases of 2.4‐fold and stimulation of liver peroxisomal acyl‐CoA oxidase mRNA were observed. Our results suggest that PPAR mRNA expression is under strict hormonal control and that the fatty acids and hormones affect PPAR mRNA levels in a manner analogous to the regulation of the peroxisomal β‐oxidation enzymes. The PPAR gene‐regulating unit apparently contains hormone‐response elements (HRE) for dexamethasone and insulin, which are thus functionally important for PPAR transcription in liver cells, making a significant enhancement or inhibition of the physiological actions of fatty acids possible. Copyright © 1994, Wiley Blackwell. All rights reserved