title: Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease.
abstract: OBJECTIVE
  The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the obesity pandemic. We analyzed the transcriptional profiles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and phenotypes and functional characteristics of adipocyte tissue macrophages (ATMs), in obese patients undergoing bariatric surgery.
  
  
  METHODS
  We collected anthropometric data; plasma samples; and SAT, VAT, and liver tissues from 113 obese patients undergoing bariatric surgery at academic hospitals in Europe (Antwerp and Leuven) and South Africa. Based on clinical and histologic features, patients were assigned to the following groups: obese, NAFLD, nonalcoholic steatohepatitis (NASH), or NASH with fibrosis. Microarray analyses were performed to identify genes expressed differentially among groups. We measured levels of cytokines and chemokines in plasma samples and levels of RNAs in adipose tissues by quantitative reverse-transcription polymerase chain reaction. ATMs were isolated from patients and 13 lean individuals undergoing cholecystectomy (controls), analyzed by flow cytometry, and cultured; immunophenotypes and levels of cytokines and chemokines in supernatants were determined.
  
  
  RESULTS
  We observed increased expression of genes that regulate inflammation in adipose tissues from patients with NAFLD and NASH; expression of these genes increased as disease progressed from NAFLD to NASH. We found 111 genes associated with inflammation that were expressed differentially between VAT and SAT. Serum levels of interleukin 8, chemokine (C-C motif) ligand 3, and tumor necrosis factor-α correlated with liver inflammation and NAFLD activity score. We developed 2 models that could be used to determine patients' liver histology based on gene expression in VAT and SAT. Flow cytometry showed increased proportions of CD11c+CD206+ and CCR2+ macrophages in VAT from patients with NASH, and supernatants of cultured macrophages had increased levels of cytokines and chemokines compared with controls.
  
  
  CONCLUSIONS
  VAT and SAT from patients with NAFLD and NASH have an increased expression of genes that regulate inflammation, and ATM produce increased levels of inflammatory cytokines, compared with adipose tissues from controls. We identified an expression profile of 5 genes in SAT that accurately predict liver histology in these patients. Transcript profiling: accession numbers: GSE58979 and GSE59045.
authors.affiliation: Laboratory of Hepatology, Faculty of Medicine, University of Leuven, Leuven, Belgium; Department of Immunology, Hepatology and GI Research Laboratory, University of Pretoria, Pretoria, South Africa.
authors.forename: Johannie
authors.initials: J
authors.lastname: du Plessis
authors.affiliation: Laboratory of Hepatology, Faculty of Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, University of Leuven, Leuven, Belgium.
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, University of Leuven, Leuven, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, University of Leuven, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: van der Schueren
authors.affiliation: Department of Abdominal Surgery, University of Leuven, Leuven, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lannoo
authors.affiliation: Department of Abdominal Surgery, University of Leuven, Leuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Oyen
authors.affiliation: Department of Abdominal Surgery, University of Leuven, Leuven, Belgium.
authors.forename: Baki
authors.initials: B
authors.lastname: Topal
authors.affiliation: Waterfall City Centre of Excellence, Waterfall City Hospital, Johannesburg, South Africa.
authors.forename: Gary
authors.initials: G
authors.lastname: Fetter
authors.affiliation: Histopathology, The Wits University Donald Gordon Medical Centre, Johannesburg, South Africa.
authors.forename: Simon
authors.initials: S
authors.lastname: Nayler
authors.affiliation: Waterfall City Centre of Excellence, Waterfall City Hospital, Johannesburg, South Africa; Department of Endocrinology, University of Pretoria, Pretoria, South Africa.
authors.forename: Tessa
authors.initials: T
authors.lastname: van der Merwe
authors.affiliation: Laboratory of Hepatology, Faculty of Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.affiliation: Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Gaal
authors.affiliation: Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Verrijken
authors.affiliation: Department of Abdominal Surgery, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Hubens
authors.affiliation: Institute of Anatomy, Leipzig University, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gericke
authors.affiliation: Laboratory of Hepatology, Faculty of Medicine, University of Leuven, Leuven, Belgium; Department of Internal Medicine, Division of Liver, Gallbladder and Pancreaticobiliary Disorders, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Francque
authors.affiliation: Laboratory of Hepatology, Faculty of Medicine, University of Leuven, Leuven, Belgium; Department of Internal Medicine, Division of Liver, Gallbladder and Pancreaticobiliary Disorders, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Laboratory of Hepatology, Faculty of Medicine, University of Leuven, Leuven, Belgium; Department of Internal Medicine, Division of Liver, Gallbladder and Pancreaticobiliary Disorders, University Hospital Gasthuisberg, Leuven, Belgium. Electronic address: schalk.vandermerwe@uzleuven.be.
authors.forename: Schalk
authors.initials: S
authors.lastname: van der Merwe
mesh_terms: D000328:Adult; D050110:Bariatric Surgery; D001530:Belgium; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology*; D050152:Intra-Abdominal Fat / Q000276:immunology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D009765:Obesity / Q000150:complications* / Q000175:diagnosis / Q000601:surgery; D020411:Oligonucleotide Array Sequence Analysis; D015434:Panniculitis / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D010641:Phenotype; D011237:Predictive Value of Tests; D012720:Severity of Illness Index; D013019:South Africa; D050151:Subcutaneous Fat / Q000276:immunology* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Gene Expression; IL8; Immune Regulation; Inflammatory Response