MicroRNAs and Nonalcoholic Steatohepatitis: A Review

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome caused by fat deposition in hepatocytes. Patients with nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD with severe fibrosis, are at high risk for liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanism of progression from simple fat deposition to NASH is complex, and previous reports have linked NAFLD to gut microbiota, bile acids, immunity, adipokines, oxidative stress, and genetic or epigenetic factors. NASH-related liver injury involves multiple cell types, and intercellular signaling is thought to be mediated by extracellular vesicles. MicroRNAs (miRNAs) are short, noncoding RNAs that play important roles as post-transcriptional regulators of gene expression and have been implicated in the pathogenesis of various diseases. Recently, many reports have implicated microRNAs in the pathogenesis of NALFD/NASH, suggesting that exosomal miRNAs are potential non-invasive and sensitive biomarkers and that the microRNAs involved in the mechanism of the progression of NASH may be potential therapeutic target molecules. We are interested in which miRNAs are involved in the pathogenesis of NASH and which are potential target molecules for therapy. We summarize targeted miRNAs associated with the etiology and progression of NASH and discuss each miRNA in terms of its pathophysiology, potential therapeutic applications, and efficacy as a NASH biomarker.

Keywords: NAFLD; NASH; NASH-derived HCC; exosomal miRNA; microRNA.

Figure 1

MiRNAs and NASH. Transcribed from genomic DNA, pri-miRNA is cleaved by Drosha and DGCR8 to form pre-miRNA. It is then bound to Exportin-5 and Ran-GTP and released into the nucleus. After these complexes of hairpin pre-miRNAs are cleaved by Dicer and TRBP, the double-stranded miRNAs are unwound. Representative miRNAs that are enhanced and attenuated during NASH progression are listed below. miRNA: microRNA; pri-miRNA: primary microRNA; DGCR8:. DiGeorge syndrome critical region 8; TRBP: transactivation response element RNA-binding 70 protein; RISC: RNA-induced silencing complex; Ago2: Argonaute 2.