Acyl coenzyme A:cholesterol acyltransferase inhibitors as hypolipidemic and antiatherosclerotic drugs.

Acyl coenzyme A:cholesterol acyltransferase (ACAT) is the enzyme that catalyzes the conversion of intracellular cholesterol into cholesteryl esters. Two ACAT isoforms, termed ACAT1 and ACAT2, have been described. ACAT1 is ubiquitously found, with high expression levels in macrophages, adrenals, sebaceous glands and foam cells from human atherosclerotic lesions. In contrast, ACAT2 expression is restricted to the intestine and the liver of mice and non-human primates. The reaction catalyzed by ACAT is essential for intestinal cholesterol absorption, synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins, and intracellular storage of cholesterol. Therefore, ACAT inhibitors would theoretically reduce plasma cholesterol levels by blocking cholesterol absorption from the diet and by reducing hepatic VLDL synthesis. Moreover, ACAT inhibition could limit the accumulation of cholesteryl esters in the cytoplasm of macrophages, thus reducing the formation of foam cells. In view of these attractive possibilities, a great deal of molecules with ACAT inhibitory properties have been synthesized in the last 20 years. However, only a few of them have reached clinical studies, mainly due to unexpected side effects. On the other hand, most of the compounds assayed in humans have not shown substantial hypolipidemic efficacy. The present article focuses on the current knowledge of the pharmacology of ACAT inhibitors, and, specifically, on the different pharmacological approaches used to evaluate these compounds as hypolipidemic and antiatherosclerotic agents.

Effect of atorvastatin on lipoprotein (a) and interleukin-10: a randomized placebo-controlled trial.

AIM: This study aimed to determine the effect of atorvastatin therapy on plasma lipoprotein (a) [Lp(a)] and biomarkers of inflammation in hypercholesterolaemic patients free of cardiovascular disease. METHODS: In this three-month randomized double-blind placebo-controlled trial, 63 hypercholesterolaemic patients were randomly treated with either placebo or atorvastatin (10 or 40 mg/day) for 12 weeks. Lp(a) and biomarkers of inflammation (C-reactive protein [CRP], interleukin [IL]-6 and -10, and tumour necrosis factor-alpha receptors [TNF-Rs]) were measured at study entry, and at four and 12 weeks of follow-up. RESULTS: At the end of the study, patients allocated to atorvastatin (10 or 40 mg/day) presented with significantly lower Lp(a) levels than those taking placebo (10 [1-41]mg/dL versus 6 [1-38]mg/dL [P = 0.02] and 21 [1-138]mg/dL versus 15 [1-103]mg/dL [P = 0.04], respectively]. In multivariate analyses, the relative changes in Lp(a) were independently related to baseline Lp(a) levels and CRP changes. No significant changes in CRP, IL-6 and TNF-Rs were observed. In contrast, IL-10 (pg/mL) increased significantly in patients taking atorvastatin (2.14 [0.49-43]pg/mL versus 4.54 [0.51-37.5]pg/mL; P = 0.01), and was even more increased with the 40-mg dose than with 10mg. CONCLUSION: Our results suggest that 12-week atorvastatin is effective in reducing Lp(a) in dyslipidaemic patients free of CVD. Furthermore, this is also the first evidence that the drug increases IL-10 in a dose-dependent manner.

Uncoupling protein-3 mRNA levels are increased in white adipose tissue and skeletal muscle of bezafibrate-treated rats.

Fibrates are hypolipidemic drugs that are also able to improve glucose tolerance in animals and diabetic patients through an unknown mechanism. Since uncoupling proteins (UCP) seem to play an important role in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether treatment of rats with bezafibrate for 3, 7, or 15 days modified UCP mRNA levels. Using RT-PCR, we observed a weak ectopic expression of UCP-1 and a 2-fold increase in UCP-3 mRNA levels in white adipose tissue after 7 and 15 days of treatment. Moreover, bezafibrate administration caused a 1. 7-fold induction in UCP-3 mRNA levels in skeletal muscle on day 7. Since UCP-3 mRNA levels are reduced in skeletal muscle of diabetic patients, this effect may be involved in the improvement of insulin sensitivity caused by bezafibrate in NIDDM.

Regulación de la expresión de caveolina-1 en macrófagos por agonistas PPAR / Regulation of caveolin-1 expression in macrophages by PPAR agonists

Introducción. La activación o la sobreexpresión del receptor activado por proliferadores peroxisómicos * (PPAR*) induce la expresión de caveolina-1 en diferentes tipos celulares. El objetivo de este estudio ha sido evaluar si los agonistas PPAR regulan la expresión de la caveolina-1 en macrófagos, y explorar los posibles mecanismos implicados. Material y métodos. Se diferenciaron monocitos THP-1 por exposición a PMA durante 24 h y, posteriormente, se trataron con rosiglitazona a diferentes dosis y durante distintos períodos. Los valores de ARNm se determinaron por la reacción de la transcriptasa inversa acoplada a la reacción en cadena de la polimerasa (RT-PCR), y la expresión de la proteína mediante western-blot. Resultados. El tratamiento con la rosiglitazona aumentó los valores de ARNm y de proteína de caveolina-1 de forma dependiente de la dosis y el tiempo en macrófagos THP-1. Esta inducción no se observó en presencia de inhibidores de la transcripción o de la síntesis de novo de proteínas. El incremento de la expresión de caveolina-1 producido por rosiglitazona no se relaciona con el estado de diferenciación celular y parece ser dependiente de la activación PPAR, ya que la presencia del antagonista PPAR GW9662 lo anuló por completo. Por último, se ha identificado un elemento de respuesta a proliferadores peroxisómicos (PPRE) funcional en el promotor del gen de la caveolina-1, que se activa por el tratamiento con rosiglitazona en macrófagos THP-1. Conclusiones. La rosiglitazona incrementa la expresión de caveolina-1 en macrófagos, a través de la activación de los PPAR y, probablemente, como consecuencia de la unión al PPRE identificado en la secuencia del promotor del gen de la caveolina-1 (AU)

Introduction. Peroxisome proliferator-activated receptor * (PPAR*) activation or overexpression induce caveolin-1 expression in several cell types. The aim of this study was to ascertain whether PPAR agonists could also regulate the caveolin-1 gene in macrophages, and to investigate the mechanisms involved. Materials and methods. PMA-treated THP-1 monocytes were incubated with rosiglitazone at different concentrations and for different periods of time. MRNA levels were determined by RT-PCR and protein expression by Western blot. Results. Our experiments demonstrated that rosiglitazone dose- and time-dependently increased caveolin-1 mRNA and protein in THP-1 macrophages. This induction was not observed in the presence of transcription inhibitors or de novo protein synthesis. We also showed that the increase in caveolin-1 elicited by rosiglitazone was not related to macrophage differentiation. This inductive effect seems to be dependent on PPAR activation, since the PPAR antagonist GW9662 abolished it. Finally, we identified a functional peroxisome proliferator response element (PPRE) in the caveolin-1 promoter, which was activated upon rosiglitazone treatment in THP-1 macrophages. Conclusions. PPAR activators, such as the PPAR* agonist rosiglitazone, increase caveolin-1 expression in macrophages. This effect appears to be mediated by PPAR activation, possibly by the binding of activated PPAR to the PPRE identified in the caveolin-1 promoter (AU)