RESUMO
AIMS: This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans. METHODS: Male obese, IR and dyslipidemic E3L.CETP mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11ß-hydroxysteroid-dehydrogenase-1 (HSD-1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4-6 weeks. The effects on bw, IR and plasma and liver lipids were assessed. RESULTS: Rosiglitazone, liraglutide and HSD-1 inhibitor significantly decreased glucose and insulin levels or IR. Liraglutide and HSD-1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high-density lipoprotein (HDL) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin. CONCLUSIONS: We conclude that the E3L.CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non-alcoholic fatty liver disease (NAFLD).
Assuntos
Apolipoproteína E3/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , Modelos Animais de Doenças , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Síndrome Metabólica/tratamento farmacológico , Camundongos Transgênicos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Animais , Atorvastatina , Fenofibrato/farmacologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Ácidos Heptanoicos/farmacologia , Humanos , Liraglutida , Masculino , Síndrome Metabólica/genética , Niacina/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/tratamento farmacológico , Obesidade/genética , Pirróis/farmacologia , Rosiglitazona , Tiazolidinedionas/farmacologiaRESUMO
p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs). Upon SMC-specific inactivation of mdm2, and not of mdm4, mice rapidly became ill and died. Necropsy showed small intestinal dilation, and histological analyses indicated a severe reduction in the number of intestinal SMCs. Increased p53 levels and activity were detected in the remaining SMCs, and the phenotype was completely rescued on a p53-null background. Interestingly, intestinal SMCs are caspase-3-negative and therefore did not undergo caspase-3-dependent apoptotic cell death. Together, Mdm2, but not Mdm4, prevents accumulation of active p53 in quiescent SMCs and thereby the induction of p53-mediated caspase-3-independent cell death.
