Differential expression of microRNAs in the visceral adipose of patients with NASH, pericellular fibrosis and type II diabetes.

摘要

Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD). NASH is one of the least understood metabolic consequences of obesity. The dysregulation of visceral adipose derived signaling molecules, including adipokines, oxidative stressors and cytokines is associated with the progression of NAFLD. MicroRNAs (miRNAs) represent a new class of post-transcriptional regulators of gene expression. These non-coding single stranded molecules are predicted to regulate a third of all human genes as they interact with certain recognition motifs found within the 3' un-translated region (UTR) of protein coding mRNAs. These interactions ultimately down regulate gene expression through mechanisms of translational repression, mRNA destabilization-mediated repression or direct mRNA degradation. In this study we profiled 664 mature miRNAs derived from the visceral white adipose tissue (WAT) of morbidly obese patients with NASH and non-NASH NAFLD. A global down-regulation of 84 mature miRNAs (Fold Change > -1.7 and P- < 0.05) was observed in patients with NASH when compared to non-NASH NAFLD controls. A total of 54 adipose derived mature miRNAs (Fold Change > -1.7 and P- < 0.05) were differentially expressed in NASH patients with pericellular fibrosis when compared to non-NASH NAFLD controls. Additionally, 6 primary transcript miRNA (pri-miRNA) assays were designed and tested for locus specific NASH related transcription. Of these, a single primary miRNA transcript, miR-7-1 ( Fold Change > 1.7 and P - < 0.01) was found to be up-regulated in NASH vs. Non-NASH NAFLD. Lastly, a systems biology analysis of NASH related miRNAs was performed to better elucidate orchestrated communication between visceral WAT and the liver, as well as the hepatic consequences of obesity related adipose remodeling. The results from our ontology enrichment analysis clearly associate a global downregulation of adipose specific miRNAs with hepatocellular carcinoma, liver neoplasms as well as chronic liver disease. Furthermore, our systems biology analysis revealed that NASH related adipose derived miRNA expression is associated with the dysegulation of the peroxisome proliferator-activated receptor (PPAR) pathway, inflammation pathways and may be associated with adiponectin reduced AMP-activated protein kinase (AMPK) signaling in the liver. This is the first study to our knowledge which links the deregulation of WAT miRNA expression and the progression of NAFLD.