The transcription factor peroxisome proliferator-activated receptor (PPAR) alpha plays an important role in lipid homeostasis. In this study, we examined whether the down-regulation of PPAR-alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure (CRF). Rats with laboratory-induced uremia by 5/6 nephrectomy were bled at 2 weeks and 10 weeks after the nephrectomy to produce conditions. For the sake of convenience, the rats observed at postoperative week 2 were defined as acute renal failure (ARF) and those observed at week 10 were defined as CRF. Lipids in lipoprotein fractions were measured by high-performance liquid chromatography. The abundance of PPAR-alpha messenger RNA (mRNA) in the liver was measured by reverse transcriptase-polymerase chain reaction. Serum creatinine and blood urea nitrogen levels rose with the progression of renal failure, but the total protein levels remained constant. Serum triglyceride in ARF rats remained unchanged from the level in sham-operated control rats, whereas that in CRF rats was 66% higher than the control level. Serum cholesterol was elevated 1.5-fold in ARF rats and 2-fold in CRF rats compared with the sham-operated counterparts. As with triglyceride, very low-density lipoprotein remained unchanged in ARF rats but rose substantially in CRF rats. All of the major lipoprotein fractions were elevated in CRF rats. These lipid and lipoprotein changes were significantly associated with creatinine and blood urea nitrogen levels. The PPAR-alpha mRNA expression in the liver was unchanged in ARF rats but was 44% lower in CRF rats. The PPAR-alpha mRNA expression was inversely correlated with serum creatinine and lipids in the overall rats. Our results indicate that PPAR-alpha mRNA expression is down-regulated in the liver of CRF rats and that this down-regulation may play a crucial role in the development of dyslipidemia.