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Inicio Clínica e Investigación en Arteriosclerosis Estudio del mecanismo de acción hipolipemiante de la lovastatina en la rata
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Vol. 15. Núm. 6.
Páginas 248-257 (Enero 2003)
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Vol. 15. Núm. 6.
Páginas 248-257 (Enero 2003)
Acceso a texto completo
Estudio del mecanismo de acción hipolipemiante de la lovastatina en la rata
Study of the mechanism of hypolipemiant effect of lovastatin in the rat
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I.C. López-Pérez, E. Relaño, E. Herrera, C. Bocos1
Autor para correspondencia
carbocos@ceu.es

Correspondencia: Dr. C. Bocos. Laboratorio de Biología Molecular. Facultad de Ciencias Experimentales y de la Salud. Universidad San Pablo-CEU. Ctra. Boadilla del Monte, km 5,300. 28668 Boadilla del Monte. Madrid. España. Correo electrónico:
Departamento de Biología Celular, Bioquímica y Biología Molecular. Facultad de Ciencias Experimentales y de la Salud. Universidad San Pablo-CEU. Madrid. España
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Información del artículo
Fundamento

Las estatinas son agents hipolipemiantes que no sólo mejoran la concentración de colesterol sino también la de triglicéridos (TG). Mientras su acción hipocolesterolemiante implica la inhibición de la colesterogénesis a través de su acción sobre la HMG-CoA reductasa, el mecanismo de su acción hipotrigliceridemiante no es tan conocido. El receptor activado por proliferadores peroxisomales tipo alfa (PPARα) es clave en el metabolismo lipídico y se ha relacionado con la afectación farmacológica de la trigliceridemia (tal es el caso de fibratos).

Métodos

El presente trabajo se ha llevado a cabo para determinar el efecto agudo de una dosis elevada de lovastatina sobre la expresión hepatica de dicho receptor en ratas normolipémicas, así como de alguno de sus genes diana. Paralelamente, se realizó un estudio ex vivo de la actividad lipolítica del tejido adiposo blanco.

Resultados

A 1,5, 3 y 7 h (tiempos de estudio) de la administración del fármaco no hubo afectación de la colesterolemia y, aunque tampoco parecía verse afectada la concentración de TG en plasma, sí que se observaba una acción hipotrigliceridemiante a las 7 h. En cuanto a las expresiones de PPARα y la de su gen diana, acil- CoA oxidasa peroxisomal (ACO), se comportaron de manera paralela, esto es, una tendencia significativa a aumentar en los animales tratados a las 7 h de la administración. En cuanto a la expresión de apolipoproteína CIII no había cambios, y la de fosfoenolpiruvato carboxicinasa (PEPCK) parecía responder bien en los dos grupos al perfil de FFA en plasma. En cuanto a la lipólisis, cuyos valores basales se incrementaron a lo largo del estudio, se veía considerablemente reducida por acción del fármaco a las 7 h, mientras que, curiosamente, a las 3 h de la administración el tejido adiposo de las ratas tratadas parecía más sensible a la adrenalina que el de las controles.

Conclusiones

Por todo ello, el efecto hipotrigliceridemiante de la lovastatina parece estar relacionado con una inducción de la expresión hepática de PPARα y de genes de la ß-oxidación peroxisomal y con un efecto antilipolítico en el tejido adiposo.

Palabras clave:
Estatinas
PPAR
Expresión génica
Lipólisis
Triglicéridos
Background

Statins are hypolipidemic drugs that not only improve cholesterol but also triglyceride levels. Whereas their cholesterol-lowering effect involves inhibition of cholesterogenesis through inhibition of enzyme 3-hidroxy-methylglutaryl CoA (HMG-CoA) reductase, the mechanism by whichthey reduce triglycerides remains unknown. Peroxisome proliferator-activated receptor alpha (PPAR-α is crucial in lipid metabolism and has been related to the pharmacologic effect on triglyceridemia (as is the case of fibrates).

Methods

This study was carried out to determine the effect of acute administration of a high dose of lovastatin on hepatic expression of both PPAR-α and some of its target genes in normolipidemic rats. In parallel, the ex vivo lipolytic activity of white adipose tissue from the same rats was also studied.

Results

Cholesterolemia was not affected by the drug at the times considered (1,5, 3 and 7 hours after administration of the drug) and, although triglyceridemia did not seem to be affected by the treatment, a hypotriglyceridemic effect was observed at 7 hours after administration. Expression of PPAR-α and its target gene, peroxisomal acyl-CoA oxidase (ACO) were similarly affected by the treatment, showing a trend to increase in treated animals. This increase was statistically significant at 7 hours. Expression of apolipoprotein CIII remained unchanged but that of phosphoenolpyruvate carboxykinase (PEPCK) seemed to be sensitive to the plasma FFA profile in both animal groups. Regarding adipose tissue lipolytic activity, the basal values, which increased throughout the study, were markedly reduced by lovastatin at 7 hours after administration. However, at 3 hours after administration adipose tissue from treated rats seemed to be more sensitive to epinephrine than tissue from control rats.

Conclusions

The results of this study suggest that the hypotriglyceridemic effect of lovastatin is related to both induction of hepatic expression of PPAR-α and genes related to peroxisomal oxidation, as well as to the antilipolytic effect on adipose tissue.

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