resumo patente de invencao: "proteinas de fusao para tratar uma sindrome metabolica". a invencao refere-se a uma proteina de fusao que compreende pelo menos um composto de fgf-21 (fator de crescimento de fibroblastos 21) e pelo menos um agonista de glp-1r (receptor de peptideo 1 tipo glucagon) bem como a composicoes farmaceuticas, utilizacoes medicas e metodos de tratamento que envolvem a proteina de fusao, em particular no campo da diabetes, dislipidemia, obesidade e/ou adiposidade.

Fenofibrate (FF) lowers plasma triglycerides via PPARα activation. Here, we analyzed lipidomic changes upon FF treatment of fructose fed rats. Three groups with 6 animals each were defined as control, fructose-fed and fructose-fed/FF treated. Male Wistar Unilever Rats were subjected to 10% fructose-feeding for 20 days. On day 14, fenofibrate treatment (100 mg/kg p.o.) was initiated and maintained for 7 days. Lipid species in serum were analyzed using mass spectrometry (ESI-MS/MS; LC-FT-MS, GC-MS) on days 0, 14 and 20 in all three groups. In addition, lipid levels in liver and intestine were determined. Short-chain TAGs increased in serum and liver upon fructose-feeding, while almost all TAG-species decreased under FF treatment. Long-chain unsaturated DAG-levels (36:1, 36:2, 36:4, 38:3, 38:4, 38:5) increased upon FF treatment in rat liver and decreased in rat serum. FAs, especially short-chain FAs (12:0, 14:0, 16:0) increased during fructose-challenge. VLDL secretion increased upon fructose-feeding and together with FA-levels decreased to control levels during FF treatment. Fructose challenge of de novo fatty acid synthesis through fatty acid synthase (FAS) may enhance the release of FAs ≤16:0 chain length, a process reversed by FF-mediated PPARα-activation.

Phosphatidylinositol-5-phosphate 4-kinase, type II, beta (PIP5K2B) is linked to the pathogenesis of obesity, insulin resistance and diabetes. Here, we describe the identification of a novel pyrimidine-2,4-diamine PIP5K2B inhibitor, designated SAR088. The compound was identified by high-throughput screening and subsequently characterized in vitro and in vivo. SAR088 showed reasonable potency, selectivity and physicochemical properties in enzymatic and cellular assays. In vivo, SAR088 lowered blood glucose levels of obese and hyperglycemic male Zucker diabetic fatty rats treated for 3 weeks. Thus, SAR088 represents the first orally available and in vivo active PIP5K2B inhibitor and provides an excellent starting point for the development of potent and selective PIP5K2B inhibitors for the treatment of insulin resistance and diabetes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE*3Leiden.CETP mice. Mice received a Western-type diet and were treated with alirocumab (3 or 10 mg/kg, weekly subcutaneous dosing) alone and in combination with atorvastatin (3.6 mg/kg/d) for 18 weeks. Alirocumab alone dose-dependently decreased total cholesterol (−37%; −46%, P < 0.001) and TGs (−36%; −39%, P < 0.001) and further decreased cholesterol in combination with atorvastatin (−48%; −58%, P < 0.001). Alirocumab increased hepatic LDL receptor protein levels but did not affect hepatic cholesterol and TG content. Fecal output of bile acids and neutral sterols was not changed. Alirocumab dose-dependently decreased atherosclerotic lesion size (−71%; −88%, P < 0.001) and severity and enhanced these effects when added to atorvastatin (−89%; −98%, P < 0.001). Alirocumab reduced monocyte recruitment and improved the lesion composition by increasing the smooth muscle cell and collagen content and decreasing the macrophage and necrotic core content. Alirocumab dose-dependently decreases plasma lipids and, as a result, atherosclerosis development, and it enhances the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice. In addition, alirocumab improves plaque morphology.

Introduction: Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease responsible for low density lipoprotein receptor (LDLR) degradation in the liver, thereby increasing LDL cholesterol levels. PCSK9 inhibition is a potential novel strategy for treatment of CVD, especially in combination with statins which increase PCSK9 expression. Alirocumab (also known as SAR236553/REGN727) is a fully human PCSK9 monoclonal antibody currently in phase 3 clinical development. Hypothesis: Alirocumab alone reduces progression of atherosclerosis in APOE*3Leiden.CETP mice and adds to the atheroprotective effect of atorvastatin in this model. Methods: Mice were fed a Western-type diet alone or were treated by weekly subcutaneous injection with alirocumab (3 or 10 mg/kg) with or without atorvastatin (3.6 mg/kg/d) for 18 weeks. Effects on plasma lipids, hepatic LDLR expression and atherosclerotic lesion size and severity were assessed. Results: Alirocumab dose-dependently decreased total cholesterol (TC) (-37% to -46%, P Conclusions: A PCSK9 monoclonal antibody, alirocumab, dose-dependently decreases plasma lipids and progression of atherosclerosis and enhances the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice.