Lack of hypotriglyceridemic effect of gemfibrozil as a consequence of age-related changes in rat liver PPARalpha.
We have investigated if changes in hepatic lipid metabolism produced by old age are related to changes in liver peroxisome proliferator-activated receptor alpha (PPARalpha). Our results indicate that 18-month-old rats showed a marked decrease in the expression and activity of liver PPARalpha, as shown by significant reductions in PPARalpha mRNA, protein and binding activity, resulting in a reduction in the relative mRNA levels of PPARalpha target genes, such as liver-carnitine-palmitoyl transferase-I (CPT-I) and mitochondrial medium-chain acyl-CoA dehydrogenase (MCAD). Further, in accordance with a liver PPARalpha deficiency in old rats, treatment of old animals with a therapeutic dose of gemfibrozil (GFB) (3mg/kg per day, 21 days) was ineffective in reducing plasma triglyceride concentrations (TG), despite attaining a 50% reduction in TG when GFB was administered to young animals at the same dose and length of treatment. We hypothesize that the decrease in hepatic PPARalpha can be related to a state of leptin resistance present in old animals.
Sanguino
Elena
E
Facultad de Farmacia, Unidad de Farmacología y Farmacognosia, Universidad de Barcelona, Avda Diagonal 643, 08028, Barcelona, Spain.
Ramón
Miguel
M
Michalik
Liliane
L
Wahli
Walter
W
Alegret
Marta
M
Sánchez
Rosa M
RM
Vázquez-Carrera
Manuel
M
Laguna
Juan C
JC
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology*; D015870:Gene Expression; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D000960:Hypolipidemic Agents; D020738:Leptin; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D042962:Acyl-CoA Oxidase; D015248:Gemfibrozil