RESUMEN
BACKGROUND: The focus of studies on high-density lipoproteins (HDL) has shifted from HDL-cholesterol (HDL-C) to HDL function. We recently demonstrated that low USF1 expression in mice and humans associates with high plasma HDL-C and low triglyceride levels, as well as protection against obesity, insulin resistance, and atherosclerosis. Here, we studied the impact of USF1 deficiency on HDL functional capacity and macrophage atherogenic functions, including inflammation, cholesterol efflux, and cholesterol accumulation. METHODS: We used a congenic Usf1 deficient mice in C57Bl/6JRccHsd background and blood samples were collected to isolate HDL for structural and functional studies. Lentiviral preparations containing the USF1 silencing shRNA expression vector were used to silence USF1 in human THP-1 and Huh-7 cells. Cholesterol efflux from acetyl-LDL loaded THP-1 macrophages was measured using HDL and plasma as acceptors. Gene expression analysis from USF1 silenced peritoneal macrophages was carried out using Affymetrix protocols. RESULTS: We show that Usf1 deficiency not only increases HDL-C levels in vivo, consistent with elevated ABCA1 protein expression in hepatic cell lines, but also improves the functional capacity of HDL particles. HDL particles derived from Usf1 deficient mice remove cholesterol more efficiently from macrophages, attributed to their higher contents of phospholipids. Furthermore, silencing of USF1 in macrophages enhanced the cholesterol efflux capacity of these cells. These findings are consistent with reduced inflammatory burden of USF1 deficient macrophages, manifested by reduced secretion of pro-inflammatory cytokines MCP-1 and IL-1ß and protection against inflammation-induced macrophage cholesterol accumulation in a cell-autonomous manner. CONCLUSIONS: Our findings identify USF1 as a novel factor regulating HDL functionality, showing that USF1 inactivation boosts cholesterol efflux, reduces macrophage inflammation and attenuates macrophage cholesterol accumulation, linking improved macrophage cholesterol metabolism and inflammatory pathways to the antiatherogenic function of USF1 deficiency.
Asunto(s)
HDL-Colesterol/genética , Colesterol/genética , Lipoproteínas HDL/genética , Factores Estimuladores hacia 5'/genética , Transportador 1 de Casete de Unión a ATP/genética , Animales , Quimiocina CCL2/genética , Colesterol/sangre , Expresión Génica/genética , Humanos , Inflamación/sangre , Inflamación/genética , Inflamación/patología , Resistencia a la Insulina/genética , Lipoproteínas HDL/sangre , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/patología , Masculino , Ratones , Ratones Noqueados , Obesidad/sangre , Obesidad/genética , Obesidad/patologíaRESUMEN
OBJECTIVE: Association of maternal angiopoietin-like protein 6 (Angptl6) levels with subsequent development of pregnancy-induced hypertension (PIH). METHODS: At 24 and 32 weeks of gestation in 47 relatively overweight (BMI ≥ 24 kg/m(2)), nulliparous pregnant women serum concentrations of Angptl6 were quantified prospectively. Insulin sensitivity and lipids were measured at 24 weeks. RESULTS: Angptl6 levels at 24 weeks, but not at 32 weeks, were significantly higher in women with subsequent PIH. Metabolic factors at 24 weeks did not correlate with Angptl6 levels. CONCLUSION: This preliminary study suggests that in the second trimester, Angptl6 levels are higher in women with subsequent PIH.