title: A liver-specific long noncoding RNA with a role in cell viability is elevated in human nonalcoholic steatohepatitis.
abstract: Hepatocyte apoptosis in nonalcoholic steatohepatitis (NASH) can lead to fibrosis and cirrhosis, which permanently damage the liver. Understanding the regulation of hepatocyte apoptosis is therefore important to identify therapeutic targets that may prevent the progression of NASH to fibrosis. Recently, increasing evidence has shown that long noncoding (lnc) RNAs are involved in various biological processes and that their dysregulation underlies a number of complex human diseases. By performing gene expression profiling of 4,383 lncRNAs in 82 liver samples from individuals with NASH (n = 48), simple steatosis but no NASH (n = 11), and healthy controls (n = 23), we discovered a liver-specific lncRNA (RP11-484N16.1) on chromosome 18 that showed significantly elevated expression in the liver tissue of NASH patients. This lncRNA, which we named lnc18q22.2 based on its chromosomal location, correlated with NASH grade (r = 0.51, P = 8.11 × 10-7), lobular inflammation (r = 0.49, P = 2.35 × 10-6), and nonalcoholic fatty liver disease activity score (r = 0.48, P = 4.69 × 10-6). The association of lnc18q22.2 to liver steatosis and steatohepatitis was replicated in 44 independent liver biopsies (r = 0.47, P = 0.0013). We provided a genetic structure of lnc18q22.2 showing an extended exon 2 in liver. Knockdown of lnc18q22.2 in four different hepatocyte cell lines resulted in severe phenotypes ranging from reduced cell growth to lethality. This observation was consistent with pathway analyses of genes coexpressed with lnc18q22.2 in human liver or affected by lnc18q22.2 knockdown.
  
  
  
  We identified an lncRNA that can play an important regulatory role in liver function and provide new insights into the regulation of hepatocyte viability in NASH. (Hepatology 2017;66:794-808).
authors.affiliation: Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.|Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Biljana
authors.initials: B
authors.lastname: Atanasovska
authors.affiliation: Department of Surgery, University Hospital Maastricht, and Nutrition and Toxicology Research Institute, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Sander S
authors.initials: SS
authors.lastname: Rensen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marijke R
authors.initials: MR
authors.lastname: van der Sijde
authors.affiliation: Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Glenn
authors.initials: G
authors.lastname: Marsman
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Iris
authors.initials: I
authors.lastname: Jonkers
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Sebo
authors.initials: S
authors.lastname: Withoff
authors.affiliation: Departments of Molecular Genetics, Molecular Cell Biology, and Population Genetics, Nutrition and Toxicology Research Institute, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
authors.affiliation: Department of Surgery, Zuyderland Medical Center, Heerlen, The Netherlands.
authors.forename: Jan Willem M
authors.initials: JWM
authors.lastname: Greve
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, Groningen, The Netherlands.|Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Klaas Nico
authors.initials: KN
authors.lastname: Faber
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, Groningen, The Netherlands.|Department of Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Han
authors.initials: H
authors.lastname: Moshage
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
authors.affiliation: Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Department of Pediatrics, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.|Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001707:Biopsy, Needle; D002470:Cell Survival / Q000235:genetics*; D002478:Cells, Cultured / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D046228:Microarray Analysis; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D062085:RNA, Long Noncoding / Q000235:genetics*; D018570:Risk Assessment; D012494:Sampling Studies
chemical_list: D062085:RNA, Long Noncoding