RESUMEN
The apolipoprotein apoC-III plays an important role in plasma triglyceride metabolism. It is predominantly produced in liver, and its hepatic expression is inhibited by insulin. To elucidate the inhibitory mechanism of insulin in apoC-III expression, we delivered forkhead box O1 (Foxo1) cDNA to hepatocytes by adenovirus-mediated gene transfer. Foxo1 stimulated hepatic apoC-III expression and correlated with the ability of Foxo1 to bind to its consensus site in the apoC-III promoter. Deletion or mutation of the Foxo1 binding site abolished insulin response and Foxo1-mediated stimulation. Likewise, Foxo1 also mediated insulin action on intestinal apoC-III expression in enterocytes. Furthermore, elevated Foxo1 production in liver augmented hepatic apoC-III expression, resulting in increased plasma triglyceride levels and impaired fat tolerance in mice. Transgenic mice expressing a constitutively active Foxo1 allele exhibited hypertriglyceridemia. Moreover, we show that hepatic Foxo1 expression becomes deregulated as a result of insulin deficiency or insulin resistance, culminating in significantly elevated Foxo1 production, along with its skewed nuclear distribution, in livers of diabetic NOD or db/db mice. While loss of insulin response is associated with unrestrained apoC-III production and impaired triglyceride metabolism, these data suggest that Foxo1 provides a molecular link between insulin deficiency or resistance and aberrant apoC-III production in the pathogenesis of diabetic hypertriglyceridemia.
Asunto(s)
Apolipoproteínas C/metabolismo , Insulina/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Triglicéridos/metabolismo , Adenoviridae/genética , Alelos , Animales , Apolipoproteínas C/sangre , Apolipoproteínas C/efectos de los fármacos , Apolipoproteínas C/genética , Sitios de Unión/genética , Células CACO-2 , Línea Celular , Células Cultivadas , Relación Dosis-Respuesta a Droga , Enterocitos/metabolismo , Genes Reporteros , Hepatocitos/metabolismo , Humanos , Hipertrigliceridemia/genética , Insulina/farmacología , Luciferasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Endogámicos , Ratones Transgénicos , Regiones Promotoras Genéticas , Ratas , Triglicéridos/sangreRESUMEN
The aim of the present study was to assess the effect of vegetal oils obtained from Pinus pinaster and P. koraiensis seeds on plasma lipoprotein levels and apolipoprotein (apo) gene expression in rats. These oils contain two particular fatty acids of the delta5-unsaturated polymethylene-interrupted fatty acid (delta5-UPIFA) family: all-cis-5,9,12-1 8:3 (pinolenic) and/or all-cis-5,11,14-20:3 (sciadonic) acids. Rats were fed for 28 d a diet containing 5% (w/w) oil supplement. Two control diets were prepared to match the fatty acid composition of P. pinaster or P. koraiensis oils with the exception of delta5-UPIFA, which were replaced by oleic acid. Pinus pinaster seed oil decreased serum triglycerides by 30% (P < 0.02), very low density lipoprotein (VLDL)-triglycerides by 40% (P < 0.01), and VLDL-cholesterol by 33% (P < 0.03). Pinus koraiensis seed oil decreased serum triglycerides by 16% [not statistically significant (ns)] and VLDL-triglycerides by 21% (ns). Gel permeation chromatography and nondenaturating polyacrylamide gel electrophoresis showed a tendency of high density lipoprotein to shift toward larger particles in pine seed oil-supplemented rats. Finally, P. pinaster seed oil treatment was associated with a small decrease of liver apoC-III (P < 0.02) but not in apoE, apoA-I, or apoA-II mRNA levels. The levels of circulating apo were not affected by pine seed oil supplementation. In conclusion, P. pinaster seed oil has a triglyceride-lowering effect in rats, an effect that is due to a reduction in circulating VLDL.
Asunto(s)
Lipoproteínas/metabolismo , Aceites de Plantas/farmacología , Animales , Apolipoproteína C-III , Apolipoproteínas C/efectos de los fármacos , Apolipoproteínas C/genética , Peso Corporal/efectos de los fármacos , Cromatografía en Gel , Suplementos Dietéticos , Ingestión de Alimentos/efectos de los fármacos , Hipolipemiantes/farmacología , Lípidos/análisis , Lípidos/sangre , Lípidos/química , Lipoproteínas/sangre , Lipoproteínas/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , ÁrbolesRESUMEN
We have examined the effect of trifluoroethanol (TFE) on the solution behaviour of three amphipathic peptides. One of the peptides, containing three heptad repeat units (Ac-YS-(AKEAAKE)3GAR-NH2), remained monomeric under conditions where TFE induced a two-state transition from a random coil to an alpha-helix. In contrast, the TFE-induced alpha-helical formation of two peptides derived from human apolipoproteins C-II and E was accompanied by the formation of discrete dimers and trimers, respectively. The apolipoprotein C-II peptide further aggregated to form beta-sheet at higher concentrations of TFE (50% v/v). The results suggest a class of peptides capable of discrete self-association in the presence of cosolvents which favour intramolecular hydrogen bonding.