BioProject

Nonalcoholic fatty liver disease (NAFLD) is a rapidly increasing global health problem that is associated with metabolic disorders covering a broad spectrum of pathological abnormalities, including simple steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis, and hepatocellular carcinoma (HCC). More...

Nonalcoholic fatty liver disease (NAFLD) is a rapidly increasing global health problem that is associated with metabolic disorders covering a broad spectrum of pathological abnormalities, including simple steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis, and hepatocellular carcinoma (HCC). Telmisartan is a potential treatment for NAFLD due to its ability to improve insulin sensitivity and decrease hepatic fat accumulation via modulation of peroxisome proliferator-activated receptor gamma (PPARγ), and to suppress hepatic fibrosis by blocking angiotensin II receptors. However, the underlying molecular mechanisms of action of telmisartan, and the interaction between the renin-angiotensin system (RAS) and PPAR, have yet to be fully elucidated. Thus, in the present study, NASH-HCC STAM mice received daily administrations of telmisartan for 6 weeks to assess the prevention of fibrosis and lipid accumulation in the liver, and to evaluate improvements in NASH. Hepatic transcriptome analyses revealed that the amelioration of NASH likely occurred through the regulation of inflammatory- and fibrosis-related gene responses. An integrated protein-protein interaction network analysis including transcriptional and non-transcriptional genes regulated by telmisartan showed that the NAFLD pathway is located at the center of the network and has interconnections with the RAS and PPAR signaling pathways. Additionally, the downstream targets of the transcription factors in the network, PPARα, PPARδ, and RELA, significantly overlapped with telmisartan-induced differentially expressed genes (DEGs). This alternative approach to assessing the transcriptome provided the opportunity to understand the fundamental molecular mechanisms underpinning the therapeutic effects of telmisartan, and will contribute to the establishment of a novel pharmacological treatment for NASH patients. Overall design: Total RNA was extracted from the frozen liver tissues with a RNeasy mini kit (Qiagen, Hilden, Germany). Following quantitative and qualitative evaluations performed with BioAnalyzer (Agilent, Santa Clara, CA, USA), RNA samples with an RNA integrity number (RIN) ≥ 6.7 and A260/A280 values ≥ 1.88 were subjected to cDNA synthesis, performed with the GeneChip WT cDNA synthesis and amplification kit (Applied Biosystems). Next, the cDNA was fragmented and biotin-labeled using GeneChip WT terminal labeling kit (Applied Biosystems), and approximately 5.5 μg of labeled cDNA was hybridized to the Affymetrix GeneChip Mouse Gene 2.0 ST Array (Affymetrix, Santa Clara, CA, USA) at 45°C for 16 h. The hybridized arrays were scanned on a GCS3000 Scanner (Affymetrix) and all data analyses were performed with the GeneChip Command Console Software (Affymetrix). All data were normalized using the robust multi-array average (RMA) approach and hierarchical clustering of the expressed probes was performed using GenePattern (https://genepattern.broadinstitute.org). The distance between clusters was computed with Pearson correlations and global gene expression profiling was conducted in triplicate for the vehicle control and telmisartan treatment groups. Less...