title: A micro-RNA expression signature for human NAFLD progression.
abstract: BACKGROUND
  The spectrum of nonalcoholic fatty liver disease (NAFLD) describes disease conditions deteriorating from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to cirrhosis (CIR) to hepatocellular carcinoma (HCC). From a molecular and biochemical perspective, our understanding of the etiology of this disease is limited by the broad spectrum of disease presentations, the lack of a thorough understanding of the factors contributing to disease susceptibility, and ethical concerns related to repeat sampling of the liver. To better understand the factors associated with disease progression, we investigated by next-generation RNA sequencing the altered expression of microRNAs (miRNAs) in liver biopsies of class III obese subjects (body mass index ≥40 kg/m(2)) biopsied at the time of elective bariatric surgery.
  
  
  METHODS
  Clinical characteristics and unbiased RNA expression profiles for 233 miRs, 313 transfer RNAs (tRNAs), and 392 miscellaneous small RNAs (snoRNAs, snRNAs, rRNAs) were compared among 36 liver biopsy specimens stratified by disease severity.
  
  
  RESULTS
  The abundances of 3 miRNAs that were found to be differentially regulated (miR-301a-3p and miR-34a-5p increased and miR-375 decreased) with disease progression were validated by RT-PCR. No tRNAs or miscellaneous RNAs were found to be associated with disease severity. Similar patterns of increased miR-301a and decreased miR-375 expression were observed in 134 hepatocellular carcinoma (HCC) samples deposited in The Cancer Genome Atlas (TCGA).
  
  
  CONCLUSIONS
  Our analytical results suggest that NAFLD severity is associated with a specific pattern of altered hepatic microRNA expression that may drive the hallmark of this disorder: altered lipid and carbohydrate metabolism. The three identified miRNAs can potentially be used as biomarkers to access the severity of NAFLD. The persistence of this miRNA expression pattern in an external validation cohort of HCC samples suggests that specific microRNA expression patterns may permit and/or sustain NAFLD development to HCC.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Surgery, Vanderbilt University, MRBIV 8465A Langford Hall, 2213 Garland Ave, Nashville, TN, 37232, USA.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Quanghu
authors.initials: Q
authors.lastname: Sheng
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Shilin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Wattacheril
authors.affiliation: Department of Surgery, Vanderbilt University, MRBIV 8465A Langford Hall, 2213 Garland Ave, Nashville, TN, 37232, USA. robb.flynn@vanderbilt.edu.
authors.forename: Charles Robb
authors.initials: CR
authors.lastname: Flynn
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000737:chemistry*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry*; D008297:Male; D035683:MicroRNAs / Q000032:analysis*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000150:complications; D012335:RNA, Ribosomal / Q000032:analysis; D020537:RNA, Small Nucleolar / Q000032:analysis; D012343:RNA, Transfer / Q000032:analysis; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; C522425:MIRN34 microRNA, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D012335:RNA, Ribosomal; D020537:RNA, Small Nucleolar; D012343:RNA, Transfer
keywords: HCC; Hepatocellular carcinoma; NAFLD; NASH; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; miRNA