Apolipoprotein A5 (apoA5) has been implicated in the formation of hepatocyte lipid droplets, a histological hallmark of non-alcoholic fatty liver disease (NAFLD). Recent evidence demonstrated that liver X receptor α (LXRα), a transcription factor involved in down-regulation of APOA5 mRNA, is activated by AMP-activated protein kinase (AMPK) that contributes to metformin-related antihyperglycemic effects. In this study we investigated the role of apoA5 and AMPK/LXRα signaling pathway in metformin-related improvement of NAFLD. Leptin-deficient (ob/ob) obese mice with NAFLD were treated with metformin, and signaling pathways were compared with non-metformin treated mice. Additionally, we determined cellular apoA5 and triglyceride (TG) levels in mouse hepatocytes in vitro and the effects of metformin, with or without an AMPK inhibitor or LXRα siRNA, on these levels. We found that metformin dose-dependently ameliorated hepatosteatosis and liver dysfunction in ob/ob mice, with a significant reduction in hepatic apoA5 expression and TG level. Metformin also dose-dependently increased phosphorylation of hepatic AMPK and LXRα in ob/ob mice. Similarly, metformin decreased apoA5 expression and TG level in mouse hepatocytes, with increased phosphorylation of cellular AMPK and LXRα. Addition of AMPK inhibitor or siRNA knockdown of LXRα significantly attenuated metformin-induced down-regulation of cellular apoA5 expression and TG level. AMPK inhibitor also significantly inhibited metformin-induced LXRα phosphorylation in these hepatocytes. Therefore, our findings indicate that metformin improves obesity-related NAFLD via inhibition of hepatic apoA5 synthesis as part of the AMPK/LXRα signaling pathway.

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Background: The current research aimed to expound the genes and pathways that are involved in coronary artery disease (CAD) and ischaemic stroke (IS) and the related mechanisms. Methods: Two array CAD datasets of (GSE66360 and GSE97320) and an array IS dataset (GSE22255) were downloaded. Differentially expressed genes (DEGs) were identified using the limma package. The online tool Database for Annotation, Visualization and Integrated Discovery (DAVID) (version 6.8; david.abcc.ncifcrf.gov) was used to annotate the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses of the DEGs. A protein-protein interaction (PPI) network was constructed by Cytoscape software, and then Molecular Complex Detection (MCODE) analysis was used to screen for hub genes. The hub genes were also confirmed by RT-qPCR and unconditional logistic regression analysis in our CAD and IS patients.