title: Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity.
abstract: OBJECTIVE
  Non-alcoholic fatty liver disease (NAFLD) is an obesity-associated disease, and in obesity adipokines are believed to be involved in the development of NAFLD. However, it is still not clear whether adipokines in the liver and/or adipose tissues can be related to the development of specific characteristics of NAFLD, such as steatosis and inflammation. We aimed to address this question by simultaneously examining the adipokine expression in three tissue types in obese individuals.
  
  
  METHODS
  We enrolled 93 severely obese individuals with NAFLD, varying from simple steatosis to severe non-alcoholic steatohepatitis. Their expression of 48 adipokines in the liver, visceral and subcutaneous adipose tissue (SAT) was correlated to their phenotypic features of NAFLD. We further determined whether the correlations were tissue specific and/or independent of covariates, including age, sex, obesity, insulin resistance and type 2 diabetes (T2D).
  
  
  RESULTS
  The expression of adipokines showed a liver- and adipose tissue-specific pattern. We identified that the expression of leptin, angiopoietin 2 (ANGPT2) and chemerin in visceral adipose tissue (VAT) was associated with different NAFLD features, including steatosis, ballooning, portal and lobular inflammation. In addition, the expression of tumor necrosis factor (TNF), plasminogen activator inhibitor type 1 (PAI-1), insulin-like growth factor 1 (somatomedin C) (IGF1) and chemokine (C-X-C motif) ligand 10 (CXCL10) in the liver tissue and the expression of interleukin 1 receptor antagonist (IL1RN) in both the liver and SAT were associated with NAFLD features. The correlations between ANGPT2 and CXCL10, and NAFLD features were dependent on insulin resistance and T2D, but for the other genes the correlation with at least one NAFLD feature remained significant after correcting for the covariates.
  
  
  CONCLUSIONS
  Our results suggest that in obese individuals, VAT-derived leptin and chemerin, and hepatic expression of TNF, IGF1, IL1RN and PAI-1 are involved in the development of NAFLD features. Further, functional studies are warranted to establish a causal relationship.
authors: Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: M G M
authors: MG
authors: Wolfs
authors: Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: N
authors: N
authors: Gruben
authors: Department of General Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands.
authors: S S
authors: SS
authors: Rensen
authors: Department of General Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands.
authors: F J
authors: FJ
authors: Verdam
authors: Department of General Surgery, Maastricht University Medical Center, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands.
authors: J W
authors: JW
authors: Greve
authors: 1] Department of Pathology, Maastricht University Medical Centre, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht, The Netherlands [2] Department of Pathology, University Hospital Antwerp, Edegem, Belgium.
authors: A
authors: A
authors: Driessen
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: C
authors: C
authors: Wijmenga
authors: School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors: W A
authors: WA
authors: Buurman
authors: 1] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK.
authors: L
authors: L
authors: Franke
authors: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: L
authors: L
authors: Scheja
authors: Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: D P Y
authors: DP
authors: Koonen
authors: Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands.
authors: R
authors: R
authors: Shiri-Sverdlov
authors: 1] Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: T W
authors: TW
authors: van Haeften
authors: Molecular Genetics Section, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: M H
authors: MH
authors: Hofker
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: J
authors: J
authors: Fu