Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

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  Figure 1. Flow chart of work undertaken. Literature mining was performed using the https://pescador.uni.lu/ tool, a web resource that allows exploring interactions between genes and proteins by identifying the co‐occurrences of their terms in data extracted from the National Center for Biotechnology Information's PubMed database. The NAFLD interaction network was modeled using the resource http://visant.bu.edu/. LncRNA2Target40 (http://bio-annotation.cn/lncrna2target/) and LncRNA2Function40 (http://bio-annotation.cn/lncrna2target/) were used to explore and prioritize lncRNA−mRNA interactions. LncRNA2Function identifies protein‐coding genes that are significantly co‐expressed with one or more lncRNAs across 19 normal human tissues; target genes of an lncRNA are defined as the differentially expressed genes after knocking down or overexpressing the lncRNA. The function of the candidate lncRNA MALAT1 was explored using the http://cbrc.kaust.edu.sa/farna tool, a knowledge base of inferred functions of 10,289 human noncoding RNA transcripts (comprising 2,734 microRNAs and 7,555 lncRNAs) in 119 human tissues and 177 primary cells. Pathway analysis was performed using the…

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  Figure 2. Up‐regulation of liver MALAT1 levels stratifies patients into the histologic phenotypes associated with disease severity. (A) Liver abundance of MALAT1 is significantly associated with NAFLD histologic severity. Each bar represents mean ± SE values. In each sample, liver abundance of MALAT1 was expressed as normalized by the liver expression levels of a housekeeping gene (RPL19 mRNA). Fold change pertains to the increase in NASH with respect to NAFL. Human expression analysis was conducted in two stages. Discovery set (NAFLD morbidly obese, sample size n = 47 [NAFL n = 32, NASH n = 15]) and control group (n = 13); and replication set (NAFLD‐MetS, sample size n = 49, NAFL n = 15, NASH n = 34). P value denotes statistical significance ascertained with analysis of variance adjusted by age, homeostasis model assessment of insulin resistance, and BMI; #P, NASH versus NAFL within groups; *P, NASH versus control subjects in morbidly obese category; nonparametric Mann‐Whitney U test. (B) Liver MALAT1 expression levels are significantly associated with the full spectrum of NAFLD histologic severity. The severity of histologic features was graded according to scores described by Brunt et…

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  Figure 3. MALAT1 up‐regulation is a common molecular event in immune response‐mediated chronic inflammatory liver damage. (A) MALAT1 expression in chronic liver diseases. MALAT1 expression in the liver of patients with NAFLD and MetS (NAFL and NASH, n = 49), therapy naive subjects with chronic HCV infection (n = 44), and patients with autoimmune liver diseases (primary biliary cholangitis and autoimmune hepatitis, n = 21). Each bar represents mean ± SE values. In each sample, liver abundance of MALAT1 was expressed as normalized by the liver expression levels of a housekeeping gene (RPL19 mRNA). The P value is the statistical significance indicated by the nonparametric Mann‐Whitney U test. (B) MALAT1 liver expression significantly correlates with VEGFA mRNA levels. Correlation between log‐transformed liver MALAT1 RNA and log‐transformed VEGFA mRNA expression levels. Liver abundance of both transcripts is expressed as normalized by the liver expression levels of a housekeeping gene (RPL19 mRNA). The P value stands for Spearman R for nontransformed variables. (C) MALAT1 gene network pathways. Pathway was predicted by the resource http://www.pantherdb.org/pathway/ version 12.0, released on…