The apolipoprotein A5 gene (APOA5) has been repeatedly implicated in lowering plasma triglyceride levels. Since several studies have demonstrated that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 is regulated by insulin. Here, we show that cell lines and mice treated with insulin down-regulate APOA5 expression in a dose-dependent manner. Furthermore, we found that insulin decreases human APOA5 promoter activity, and subsequent deletion and mutation analyses uncovered a functional E box in the promoter. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that this APOA5 E box binds upstream stimulatory factors (USFs). Moreover, in transfection studies, USF1 stimulates APOA5 promoter activity, and the treatment with insulin reduced the binding of USF1/USF2 to the APOA5 promoter. The inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway abolished insulin's effect on APOA5 gene expression, while the inhibition of the P70 S6 kinase pathway with rapamycin reversed its effect and increased APOA5 gene expression. Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter. Taken together, these data indicate that insulin-mediated APOA5 gene transrepression could involve a phosphorylation of USFs through the PI3K and P70 S6 kinase pathways that modulate their binding to the APOA5 E box and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in men showed a decrease in the plasma ApoAV level. These results suggest a potential contribution of the APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia.Several epidemiological studies have established that, in addition to an elevated cholesterol level in low-density lipoprotein and reduced cholesterol level in high-density lipoprotein (HDL), hypertriglyceridemia is an independent risk factor for coronary heart diseases (12, 22). Moreover, hypertriglyceridemia is often associated with the metabolic syndrome that characterizes diabetes and obesity (21,35). Type 2 diabetes is frequently linked to hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, and the leading cause of death for individuals with diabetes is cardiovascular diseases (34).The apolipoprotein A5 gene (APOA5) was identified through comparative sequence analysis of genomic DNA sequences and has been shown to be important in determining plasma triglyceride levels in mice and humans (42). This gene is mainly expressed in the liver and resides in HDL and very low density lipoprotein particles (42,59). It has been demonstrated that mice expressing a human APOA5 transgene showed a decrease in plasma triglyceride concentration to one-third the levels in control mice. Conversely, knockout mice lacking APOA5 had four times as much plasma triglycerides as controls. Moreover, adenoviral overexpression of APOA5 reduced serum levels of triglycerides and cholesterol in mice (60). Recent works focused on th...

Farnesoid X receptor (FXR) is highly expressed in liver and intestine where it controls bile acid (BA), lipid and glucose homeostasis. Here we show that FXR is expressed and functional, as assessed by target gene expression analysis, in human islets and beta-cell lines. FXR is predominantly cytosolic-localized in the islets of lean mice, but nuclear in obese mice. Compared to FXR+/+ mice, FXR-/- mice display a normal architecture and beta-cell mass but the expression of certain islet-specific genes is altered. Moreover, glucose-stimulated insulin secretion (GSIS) is impaired in the islets of FXR-/- mice. Finally, FXR activation protects human islets from lipotoxicity and ameliorates their secretory index.