Mechanism of Triclosan in the Treatment of Nonalcoholic Fatty Liver Disease Based on Network Pharmacology / 中国医学科学院学报

Objective To explore the potential targets of triclosan in the treatment of nonalcoholic fatty liver disease(NAFLD) and to provide new clues for the future research on the application of triclosan. Methods The targets of triclosan and NAFLD were obtained via network pharmacology.The protein-protein interaction network was constructed with the common targets shared by triclosan and NAFLD.The affinity of triclosan to targets was verified through molecular docking.Gene ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment were carried out to analyze the key targets and the potential mechanism of action.NAFLD model was established by feeding male C57BL/6J mice with high-fat diet for 12 weeks.The mice were randomly assigned into a model group and a triclosan group [400 mg/(kg·d),gavage once a day for 8 weeks].The hematoxylin-eosin(HE) staining was used for observation of the pathological changes and oil red O staining for observation of fat deposition in mouse liver.Western blotting was employed to detect the protein level of peroxisome proliferator-activated receptor alpha(PPARα) in the liver tissue. Results Triclosan and NAFLD had 34 common targets,19 of which may be the potential targets for the treatment,including albumin(ALB),PPARα,mitogen-activated protein kinase 8(MAPK8),and fatty acid synthase.Molecular docking predicted that ALB,PPARα,and MAPK8 had good binding ability to triclosan.KEGG pathway enrichment showcased that the targets were mainly enriched in peroxisome proliferator-activated receptor signaling pathway,in which ALB and MAPK8 were not involved.Triclosan alleviated the balloon-like change and lipid droplet vacuole,decreased the lipid droplet area,and up-regulated the expression level of PPARα in mouse liver tissue. Conclusion PPARα is a key target of triclosan in the treatment of NAFLD,which may be involved in fatty acid oxidation through the peroxisome proliferator activated receptor signaling pathway.

Receptor ativado por proliferadores de peroxissoma gama (Ppargama): estudo molecular na homeostase da glicose, metabolismo de lipídeos e abordagem terapêutica / Peroxisome proliferator-activated receptor gamma (PPARgamma): molecular study in glucose homeostasis, lipid metabolism and therapeutic approach

Os receptores ativados por proliferadores de peroxissoma (PPARs) são fatores de transcrição pertencentes à família de receptores nucleares que regulam a homeostase da glicose, metabolismo de lipídeos e inflamação. Três proteínas, codificadas por genes distintos, têm sido identificadas: PPARalfa, PPARbeta e PPARgama, que controlam a expressão gênica pela ligação a elementos responsivos específicos (PPREs) localizados na região promotora. Estudos recentes sugerem que a ativação do PPARgama pode diminuir a progressão da aterosclerose e aumentar a sensibilidade à insulina, podendo ser um potencial alvo terapêutico para o tratamento de diversas enfermidades, incluindo o diabetes melito do tipo 2 e dislipidemia. Esta revisão destaca os estudos recentes e os avanços das principais funções que esse receptor desempenha no metabolismo, com ênfase nos mecanismos moleculares e eficácia terapêutica.

The peroxisome proliferators-activated receptors (PPARs) are transcription factors belonging to the family of nuclear receptors that regulate glucose homeostasis, lipid metabolism and inflammation. Three proteins, encoded by distinct genes, have been identified: PPARalpha, PPARbeta and PPARgamma, which control gene expression by binding to specific response elements (PPREs) in the promoters. Recent studies suggest that activation of PPARgamma might decrease atherosclerosis progression and increase the insulin sensitivity, might be a potential therapeutic target for the treatment of a diverse array of disorders, including type 2 diabetes and dyslipidaemia. This review highlights recent studies, which have advanced our understanding of the pivotal role that this receptor plays in metabolism, with particular reference to the molecular mechanisms and therapeutic efficacy.