Article date: August 2005
By: Elena Sanguino, Nuria Roglans, Marta Alegret, Rosa M Sánchez, Manuel Vázquez‐Carrera, Juan C Laguna in Volume 145, Issue 7, pages 853-861
Old rats are resistant to fibrate‐induced hypolipidemia owing to a reduction in hepatic peroxisome proliferator‐activated receptor α (PPARα). We tested whether the age‐related decrease in PPARα is prevented by atorvastatin (ATV), a hypolipidemic statin.
We determined the activity and expression of Liver X receptor α (LXRα) and PPARα 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 PPARα‐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 LXRα 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 PPARα mRNA (2.2‐fold), PPARα protein (1.6‐fold), and PPARα‐binding activity.
Hepatic nuclear factor‐4 (HNF‐4) and chicken ovalbumin upstream‐transcription factor‐II participate in the transcriptional regulation of the PPARα 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 PPARα may be responsible for the improvement of the lipid metabolic phenotype produced by ATV administration to senescent male rats.
Old rats are resistant to fibrate‐induced hypolipidemia owing to a reduction in hepatic peroxisome proliferator‐activated receptor α (PPARα). We tested whether the age‐related decrease in PPARα is prevented by atorvastatin (ATV), a hypolipidemic statin.
We determined the activity and expression of Liver X receptor α (LXRα) and PPARα 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 PPARα‐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 LXRα 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 PPARα mRNA (2.2‐fold), PPARα protein (1.6‐fold), and PPARα‐binding activity.
Hepatic nuclear factor‐4 (HNF‐4) and chicken ovalbumin upstream‐transcription factor‐II participate in the transcriptional regulation of the PPARα 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 PPARα may be responsible for the improvement of the lipid metabolic phenotype produced by ATV administration to senescent male rats.
British Journal of Pharmacology (2005) 145, 853–861. doi:10.1038/sj.bjp.0706260
DOI: 10.1038/sj.bjp.0706260
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