RESUMEN
Cafestol, a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish, and cafetière coffee, is the most potent cholesterol-elevating compound known in the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of cafestol, including cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis. We have examined the mechanism by which cafestol elevates serum lipid levels. Changes in several lipid parameters were observed in cafestol-treated APOE3Leiden mice, including a significant increase in serum triglyceride levels. Microarray analysis of these mice identified alterations in hepatic expression of genes involved in lipid metabolism and detoxification, many of which are regulated by the nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR). Further studies demonstrate that cafestol is an agonist ligand for FXR and PXR, and that cafestol down-regulates expression of the bile acid homeostatic genes CYP7A1, sterol 12alpha-hydroxylase, and Na(+)-taurocholate cotransporting polypeptide in the liver of wild-type but not FXR null mice. Cafestol did not affect genes known to be up-regulated by FXR in the liver of wild-type mice, but did increase expression of the positive FXR-target genes intestinal bile acid-binding protein and fibroblast growth factor 15 (FGF15) in the intestine. Because FGF15 has recently been shown to function in an enterohepatic regulatory pathway to repress liver expression of bile acid homeostatic genes, its direct induction in the gut may account for indirect effects of cafestol on liver gene expression. PXR-dependent gene regulation of cytochrome P450 3A11 and other targets by cafestol was also only seen in the intestine. Using a double FXR/PXR knockout mouse model, we found that both receptors contribute to the cafestol-dependent induction of intestinal FGF15 gene expression. In conclusion, cafestol acts as an agonist ligand for both FXR and PXR, and this may contribute to its impact on cholesterol homeostasis.
Asunto(s)
Proteínas de Unión al ADN/agonistas , Diterpenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores de Esteroides/agonistas , Factores de Transcripción/agonistas , Animales , Apolipoproteína E3/genética , Colesterol 7-alfa-Hidroxilasa/genética , Café/química , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Diterpenos/efectos adversos , Diterpenos/metabolismo , Femenino , Factores de Crecimiento de Fibroblastos/genética , Humanos , Hipercolesterolemia/inducido químicamente , Técnicas In Vitro , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Modelos Biológicos , Receptor X de Pregnano , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/deficiencia , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Esteroides/deficiencia , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional/efectos de los fármacosRESUMEN
Myocardial right ventricular (RV) hypertrophy due to pulmonary hypertension is aimed at normalizing ventricular wall stress. Depending on the degree of pressure overload, RV hypertrophy may progress to a state of impaired contractile function and heart failure, but this cannot be discerned during the early stages of ventricular remodeling. We tested whether critical differences in gene expression profiles exist between ventricles before the ultimate development of either a compensated or decompensated hypertrophic phenotype. Both phenotypes were selectively induced in Wistar rats by a single subcutaneous injection of either a low or a high dose of the pyrrolizidine alkaloid monocrotaline (MCT). Spotted oligonucleotide microarrays were used to investigate pressure-dependent cardiac gene expression profiles at 2 wk after the MCT injections, between control rats and rats that would ultimately develop either compensated or decompensated hypertrophy. Clustering of significantly regulated genes revealed specific expression profiles for each group, although the degree of hypertrophy was still similar in both. The ventricles destined to progress to failure showed activation of pro-apoptotic pathways, particularly related to mitochondria, whereas the group developing compensated hypertrophy showed blocked pro-death effector signaling via p38-MAPK, through upregulation of MAPK phosphatase-1. In summary, we show that, already at an early time point, pivotal differences in gene expression exist between ventricles that will ultimately develop either a compensated or a decompensated phenotype, depending on the degree of pressure overload. These data reveal genes that may provide markers for the early prediction of clinical outcome as well as potential targets for early intervention.