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

SOOKOIAN, SILVIA; FLICHMAN, DIEGO; GARAYCOECHEA, MARTIN E.; SAN MARTINO, JULIO; CASTAÑO, GUSTAVO O.; PIROLA, CARLOS J.

Hepatology Communications

Wiley Periodicals, Inc. on behalf of the American Association for the Study of Liver Diseases,

Lugar: Hoboken, NJ; Año: 2018

Long noncoding RNAs (lncRNAs) are functional molecules that orchestrate gene expression. To identify lncRNAs involved in nonalcoholic fatty liver disease (NAFLD) severity, we performed a multiscale study that included: (a) systems biology modeling that indicated metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) as a candidate lncRNAfor exploring disease-related associations, (b) translational exploration in the clinical setting, and (c) mechanistic modeling.MALAT1liver profiling was performed in three consecutive phases, including an exploratory stage (liver samples from patients with NAFLD who were morbidly obese [n547] and from 13 individuals with normal liver histology); a replication stage (patients with NAFLD and metabolic syndrome [n549]); and a hypothesis-driven stage (patients with chronic hepatitis C and autoimmune liver diseases, [n565]). Liver abundance ofMALAT1was associated with NAFLD severity(P51310?6);MALAT1expression levels were up-regulated 1.75-fold (P50.029) and 3.6-fold (P50.012) in patients with nonalcoholic steatohepatitis compared to those diagnosed with simple steatosis (discovery and replication set, respectively; analysis of covariance adjusted by age, homeostasis model assessment, and body mass index). Quantification of liver vascular endothelial growth factor A messenger RNA, a target ofMALAT1, revealed a significant correlation between the two RNAs (R, 0.58;P