Bile acids (BA) are signalling molecules which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex BA in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces Glucagon-Like Peptide-1 (GLP-1) production by L-cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L-cells and controls GLP-1 production is unknown. Here we show that FXR activation in L-cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR-deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes.

Abstract-Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease (CVD). In addition to their cholesterol-lowering activities, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects not only on CVD but also on lipid-unrelated immune and inflammatory diseases, such as rheumatoid arthritis, asthma, stroke, and transplant rejection. However, the molecular mechanisms involved in these antiinflammatory properties of statins are unresolved. Here we show that the peroxisome proliferator-activated receptor (PPAR) ␣ mediates antiinflammatory effects of simvastatin in vivo in models of acute inflammation. The inhibitory effects of statins on lipopolysaccharide-induced inflammatory response genes were abolished in PPAR␣-deficient macrophages and neutrophils. Moreover, simvastatin inhibited PPAR␣ phosphorylation by lipopolysaccharide-activated protein kinase C (PKC) ␣. A constitutive active form of PKC␣ inhibited nuclear factor B transrepression by PPAR␣ whereas simvastatin enhanced transrepression activity of wild-type PPAR␣, but not of PPAR␣ mutated in its PKC phosphorylation sites. These data indicate that the acute antiinflammatory effect of simvastatin occurs via PPAR␣ by a mechanism involving inhibition of PKC␣ inactivation of PPAR␣ transrepression activity. Key Words: inflammation Ⅲ macrophages Ⅲ neutrophils Ⅲ nuclear receptors Ⅲ statins Ⅲ PKC S tatins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the ratelimiting enzyme in cholesterol synthesis, are widely prescribed for the treatment of hypercholesterolemia. 1 In addition to plasma lipid-modulating action, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects on cardiovascular disease (CVD). 2 Emerging evidences also suggest beneficial therapeutic activities of statins in immune and inflammatory diseases such as multiple sclerosis, Alzheimer's disease, ischemic stroke, transplant rejection, rheumatoid arthritis, and asthma. [3][4][5][6] Several clinical observations indicate that these effects cannot be attributed to their cholesterol-lowering activities only. 7 Statin therapy decreases plasma concentrations of inflammatory markers, such as C-reactive protein (CRP), within 1 week after treatment initiation, before any lipid changes are observed. 8 Statin treatment reduces the incidence of ischemic stroke for which plasma cholesterol levels are not considered a risk factor. 9 Moreover, statins also exert antiinflammatory actions in animal models, which are resistant to their hypolipidemic actions. 10 In models of acute and chronic inflammation, statins inhibit endothelial adhesion and transendothelial migration of leukocytes to sites of inflammation, 10 acting both on endothelial cells and leukocytes. Statins modulate macrophage functions by inhibiting the activation of inflammatory response genes, such as interleukin (IL)-1b and IL-6, tumor necrosis...

Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies.