Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis

Background and Aims Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. Approach and Results To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL(-/-)) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2(-/-)) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL(-/-) mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and beta-oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2(-/-) mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E-2 accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation. Conclusions Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis

Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats

<p>Polyethylene glycol (PEG) is a frequently used osmotic laxative that accelerates gastrointestinal transit. It has remained unclear, however, whether PEG affects intestinal functions. We aimed to determine the effect of PEG treatment on intestinal sterol metabolism. Rats were treated with PEG in drinking water (7%) for 2 wk or left untreated (controls). We studied the enterohepatic circulation of the major bile salt (BS) cholate with a plasma stable isotope dilution technique and determined BS profiles and concentrations in bile, intestinal lumen contents, and feces. We determined the fecal excretion of cholesterol plus its intestinally formed metabolites. Finally, we determined the cytolytic activity of fecal water (a surrogate marker of colorectal cancer risk) and the amount and composition of fecal microbiota. Compared with control rats, PEG treatment increased the pool size (+51%; P <0.01) and decreased the fractional turnover of cholate (-32%; P <0.01). PEG did not affect the cholate synthesis rate, corresponding with an unaffected fecal primary BS excretion. PEG reduced fecal excretion of secondary BS and of cholesterol metabolites (each P <0.01). PEG decreased the cytolytic activity of fecal water [54 (46-62) vs. 87 (85-92)% erythrocyte potassium release in PEG-treated and control rats, respectively; P <0.01]. PEG treatment increased the contribution of Verrucomicrobia (P <0.01) and decreased that of Firmicutes (P <0.01) in fecal flora. We concluded that PEG treatment changes the intestinal bacterial composition, decreases the bacterial dehydroxylation of primary BS and the metabolism of cholesterol, and increases the pool size of the primary BS cholate in rats.</p>

Característica do ambiente comunitário nos níveis de atividade física de adolescentes de Curitiba, PR

Orientador : Prof. Dr. Rodrigo Siqueira ReisDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Educação Física. Defesa: Curitiba, 24/02/2017Inclui referências : f. 108-114Resumo: RESUMO As características ambientais tem se mostrado relacionadas aos hábitos da prática de atividade física da população. Grande parte da população mundial de adolescentes não atinge os níveis recomendados de atividade física. Recentemente tem sido estudado como as características ambientais podem auxiliar na melhoria destes indicadores. No entanto, a maior parte das evidências na literatura são de países de renda elevada, o que não permite representar as características de países de renda baixa e média. Além disso, as medidas são comumente avaliadas por Sistemas de Informações Geográficas. Mensurar as características ambientais a nível de microescala podem permitir compreender melhor as características do ambiente e a prática de atividade física e proporcionar mudanças com menor custo e maior rapidez. Portanto, o objetivo deste estudo foi avaliar a associação entre atributos físicos do ambiente construído capturados pela microescala e atividade física de adolescentes de Curitiba-PR, Brasil. Os dados são oriundos de dois projetos, IPEN Adolescent (Projeto ESPAÇOS) e MAPS Global, caracterizados estudos de delineamento transversal. Foram selecionados apenas adolescentes que apresentaram informações de acelerômetro e/ou GPS válidas (n=356). Os dados da prática dos deslocamentos para a escola e pelo bairro foram autoreportados e a atividade física moderada a vigorosa obtida com dados coletados por meio de acelerômetros. As informações do ambiente construído a nível de microescala foram coletadas no projeto MAPS Global por meio de observação sistemática. As rotas avaliadas pela rede de ruas, possuíam, no mínimo 400 metros e, no máximo, 720 metros a partir da residência do adolescente até um conglomerado comercial mais próximo, distribuídas em quatro quadrantes da combinação de walkability e renda do bairro. Locais de alto walkability se mostraram positivos com a presença de locais comerciais, estética e qualidade das calçadas. O contexto da atividade física do deslocamento, para a escola ou de lazer, se mostraram associadas com a presença de características de locais não residenciais e melhor qualidade dos segmentos e de forma inversa para transportes motorizados. A atividade física moderada à vigorosa se mostrou associada apenas com a presença de "semáforos". Conclui-se que as características do bairro a nível de microescala são mais importantes para o deslocamento do que atividades de maior intensidade, que aparentemente são realizadas em locais mais específicos. Estudos com amostra representativa de adolescentes e do entorno das residências devem ser desenvolvidos para identificar as reais condições da cidade e quais domínios da atividade física podem ser associados com a microescala. Palavras-chave: Atividade motora, ambiente construído, adolescenteAbstract:Environmental characteristics showed related to the habits of the physical activity of the population. Most of the adolescents' population does not reach recommended levels of physical activity. Recently has been studied how the environmental characteristics can help to improve of these indicators. However, most of the evidence in the literature is from high-income countries, which does not allow us to represent the characteristics of low- and middle-income countries. In addition, the measurements are commonly evaluated by Geographic Information Systems (GIS). Measuring the environmental characteristics at the microscale can allow better understanding of the characteristics of the environment and the practice of physical activity and provide changes with lower costs and faster. Therefore, the objective of this study was to evaluate the association between physical attributes of the built environment captured by the microscale and physical activity of adolescents from Curitiba-PR, Brazil. The data come from two projects, IPEN Adolescent (Projeto ESPAÇOS) and MAPS Global, characterized as cross-sectional design. Only adolescents presenting valid accelerometer and / or GPS information (n=356) were selected. The data of the practice of the trips to the school and the neighborhood were self-reported and the moderate to vigorous physical activity obtained with data collected through accelerometers. Information on the environment built at the microscale level collected in the MAPS Global project through systematic observation. The routes evaluated by the street network had at least 400 meters and a maximum of 720 meters from the adolescent's residence to a nearby commercial cluster, distributed in four quadrants of the combination of walkability and income. Places of high walkability were positive with the presence of commercial sites, aesthetics and quality of the sidewalks. The context of the physical activity of the displacement, for the school or of leisure, showed to be associated with the presence of characteristics of non-residential places and better quality of the segments and of inverse form for motorized transports. Moderate to vigorous physical activity was associated only with the presence of traffic lights. Characteristics of the neighborhood at the microscale level are more important for commuting than activities of greater intensity, which apparently are performed in specific places. Studies with a representative sample of adolescents and the surroundings of the residences to identify the real conditions of the city and which domains of physical activity can be associated with the microscale. Keywords: Motor activity, built environment, adolescen