Dysregulated Expression of the Long non-coding RNA (lncRNA) MALAT1 in the Liver of Patients with Nonalcoholic fatty liver Disease (NAFLD) stratifies patients into the Histological Phenotypes Associated with the Disease Severity

MARTIN E GARAYCOECHEA; DIEGO FLICHMAN; CARLOS JOSE PIROLA; GUSTAVO CASTAÑO; CARLA GAZZI; SILVIA SOOKOIAN

Washington DC

Congreso; The 68th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2017; 2017

American Association for the Study of Liver Diseases

Background: LncRNAs orchestrate gene expression by modulating a myriad of molecular pathways. To identify lncRNAs involved in NAFLD severity we performed a multi-stage study that included: a) a systems biology screening-strategy, b) exploration of lncRNA-mRNAs interactions, and c) expression profiling of selected lnRNAs. Methods: Mining of biological interactions was performed by VisANT platform; LncRNA2Target dataset was used to predict lncRNAs-target genes interactions. Liver profiling of a candidate lncRNA was performed by qRT-PCR; RPL19 (ribosomal protein L19) was used for data normalization. Patients were selected from two different hospital-based settings, a cohort of morbid-obese subjects (mean±SD, age: 43±11 years, BMI: 51±11,) who underwent bariatric surgery (discovery-set, n=47) and a cross-sectional study of patients with NAFLD characterized by liver biopsy and Metabolic Syndrome (age: 49.7±10, BMI: 32±6.4) (replication-set, n=34).Results: The NAFLD-interaction network yield a list of 494 genes; prioritization of mRNA-lncRNAs interactions showed ten candidate-lnRNAs potentially involved in gene expression regulation. Based on assessment of tissue-specific and co-expression patterns, we selected for further exploration the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), a~7kb single-exon transcript located in Chr 11q13 that is highly conserved across species. We found that MALAT1, which is involved in a plethora of physiological processes, including regulation of cell-cycle and tumorigenesis, is constitutively expressed in the liver and the liver abundance of MALAT1 was significantly associated with NAFLD severity (p=0.00011). Specifically, liver-MALAT1 expression was significantly up-regulated by 1.75-fold (p=0.029) and 5.81-fold (p=0.0038) in patients with NASH compared with simple steatosis (SS) (discovery and replication set, respectively, ANCOVA adjusted by age, HOMA and BMI). MALAT1-expression levels significantly correlate with the full spectrum of histological severity, including the degree of steatosis (R:0.47 p=0.000007), ballooning degeneration (R:0.39 p=0.0002), lobular inflammation (R:0.30 p=0.0057) and fibrosis (R:0.45 p=0.00002). Exploration of liver VEGFα-mRNA, a proangiogenic factor driving tumor angiogenesis, which is a target of MALAT1, showed levels of both transcripts positively correlated (R:0.59, p=0.00002). Conclusion: This step-wise analysis of lncRNAs uncovered MALAT1 as implicated in the molecular pathogenesis of NASH. Dysregulated expression of MALAT1 seems to tip the transition from simple steatosis to a more aggressive phenotype. The AUROC for distinguishing NASH from SS was 0.78±0.05.