Atorvastatin reverses age-related reduction in rat hepatic PPARalpha and HNF-4.

Old rats are resistant to fibrate-induced hypolipidemia owing to a reduction in hepatic peroxisome proliferator-activated receptor alpha (PPARalpha). We tested whether the age-related decrease in PPARalpha is prevented by atorvastatin (ATV), a hypolipidemic statin. We determined the activity and expression of Liver X receptor alpha (LXRalpha) and PPARalpha in the liver of 18-month-old rats treated with 10 mg kg(-1) of ATV for 21 days. We measured fatty acid oxidation (FAO), the expression of PPARalpha-target genes, liver triglyceride (TG) and cholesteryl ester (CE) contents and plasma concentrations of TG, cholesterol, glucose, nonesterified fatty acids (NEFA), insulin and leptin. While old female rats were practically unresponsive, ATV-treated old males showed lower liver TG (-41%) and CE (-48%), and plasma TG (-35%), glucose (-18%) and NEFA (-39%). Age-related alterations in LXRalpha expression and binding activity were reverted in ATV-treated old males. These changes were related to an increase in hepatic FAO (1.2-fold), and PPARalpha mRNA (2.2-fold), PPARalpha protein (1.6-fold), and PPARalpha-binding activity. Hepatic nuclear factor-4 (HNF-4) and chicken ovalbumin upstream-transcription factor-II participate in the transcriptional regulation of the PPARalpha gene, while peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) behaves as a PPAR coactivator. Ageing reduced the hepatic content of HNF-4 (74%) and PGC-1 (77%) exclusively in male rats. ATV administration to old males enhanced the hepatic expression and binding activity (two-fold) of HNF-4. ATV-induced changes in hepatic HNF-4 and PPARalpha may be responsible for the improvement of the lipid metabolic phenotype produced by ATV administration to senescent male rats.