Altered expression of MALAT1 lncRNA in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells

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In the present study, we sought to identify long noncoding RNA (lncRNA) expression profiles in nonalcoholic steatohepatitis (NASH) patients with histologic evidence of lobular inflammation and advanced fibrosis. We profiled lncRNA expression using RNA-sequencing of wedge liver biopsies from 24 nonalcoholic fatty liver disease (NAFLD) patients with normal liver histology, 53 NAFLD patients with lobular inflammation, and 65 NAFLD patients with advanced fibrosis. Transcript profiling identified 4432 and 4057 differentially expressed lncRNAs in comparisons of normal tissue with lobular inflammation and fibrosis samples, respectively. Functional enrichment analysis revealed lncRNA participation in transforming growth factor beta 1 and tumor necrosis factor signaling, insulin resistance, and extracellular matrix maintenance. Several lncRNAs were highly expressed in fibrosis relative to normal tissue, including nuclear paraspeckle assembly transcript 1, hepatocellular carcinoma upregulated lncRNA, and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Two potential target mRNAs, syndecan 4 (SDC4), and C-X-C motif chemokine ligand 5 (CXCL5) were identified for hepatocellular carcinoma upregulated lncRNA andMALAT1, respectively, but onlyCXCL5showed differential expression among the different histologic classes. Knockdown ofMALAT1expression reduced CXCL5 transcript and protein levels by 50% and 30%, respectively, in HepG2 cells. The expression ofMALAT1andCXCL5was upregulated in activated hepatic stellate (LX-2) cells compared to cells in the quiescent state, andMALAT1expression was regulated by hyperglycemia and insulin in HepG2 cells, but only by insulin in LX-2 cells. Dysregulated lncRNA expression is associated with inflammation and fibrosis in NASH. Functionally relevant differences inMALAT1expression may contribute to the development of fibrosis in NASH through mechanisms involving inflammatory chemokines.

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