TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL ANALYSIS OF PEROXISOMAL PROTEIN-ENCODING GENES FROM RAT TREATED WITH AN HYPOLIPEMIC AGENT, CIPROFIBRATE - EFFECT OF AN INTERMITTENT TREATMENT AND INFLUENCE OF OBESITY

The treatment of rats with ciprofibrate, a potent peroxisome prolifera tor, led to increased levels of the peroxisomal acyl-CoA oxidase (AGO) mRNA. How ciprofibrate functions to elevate ACO mRNA is not known. To help determine the mechanism of ciprofibrate action, in vitro transcr iption assays were performed. It was determined that ciprofibrate was responsible for a 3.5-fold stimulation of the rate of ACO transcriptio n within 24 hr of ingestion. It was also observed that the transcripti on rate stimulation following a 2-week ciprofibrate treatment of Wista r rats was maintained following 4 weeks of ciprofibrate withdrawal. Re -introduction of the drug after the 4-week pause resulted in greater s timulation than was initially observed. The results demonstrate that t he effect of ciprofibrate is rapid and persists at least twice as long as the initial treatment period. In Zucker rats, both lean and obese, ACO mRNA levels were examined following 2 weeks of ciprofibrate treat ment (1 or 3 mg/kg body weight/day). The presence of increased blood l evels of triglycerides did not increase ciprofibrate action on transcr iption, although basal levels of transcription of peroxisomal enzymes were higher in obese rats. The increase in the ACO mRNA level was grea ter than the transcription rate stimulation suggesting a post-transcri ptional regulation.