title: Adiponectin regulates aquaglyceroporin expression in hepatic stellate cells altering their functional state.
abstract: OBJECTIVE
  Obesity is a major risk factor for liver fibrosis and tightly associated with low levels of adiponectin. Adiponectin has antifibrogenic activity protecting from liver fibrosis, which is mainly driven by activated hepatic stellate cells (HSC). Aquaporins are transmembrane proteins that allow the movement of water and, in case of aquaglyceroporins (AQPs), of glycerol that is needed in quiescent HSC for lipogenesis. Expression of various AQPs in liver is altered by obesity; however, the mechanisms through which obesity influences HSCs activation and AQPs expression remain unclear. This study aimed to identify obesity-associated factors that are related to HSC AQPs expression activation and lipid storage.
  
  
  METHODS
  Correlations between serum adipokine levels and hepatic AQPs gene expression were analyzed from a cohort of obese patients. AQP and fibrotic gene expression was determined in a HSC line (LX2) and in a hepatocyte cell line (HepG2) after stimulation with adiponectin using quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  We found that serum adiponectin significantly correlated with liver AQP3, AQP7, AQP9 gene expressions. In vitro, adiponectin induced upregulation of AQP3 gene and AQP3 protein expression in human HSCs, but not in hepatocytes, while AQP7, AQP9 remained undetectable. Accordingly, HSC stimulated with adiponectin increased glycerol uptake, lipogenic gene expression, and lipid storage while downregulating activation/fibrosis markers.
  
  
  CONCLUSIONS
  These findings demonstrate that adiponectin is a potent inhibitor of HSC activation and induces AQPs expression. Thus, low serum levels of adiponectin could be a mechanism how obesity affects the functional state of HSC, thereby contributing to obesity-associated liver fibrosis.
authors.affiliation: Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Matteo
authors.initials: M
authors.lastname: Tardelli
authors.affiliation: Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Veronica
authors.initials: V
authors.lastname: Moreno-Viedma
authors.affiliation: Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Zeyda
authors.affiliation: Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Bianca K
authors.initials: BK
authors.lastname: Itariu
authors.affiliation: Department of Surgery, Division of General Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Felix B
authors.initials: FB
authors.lastname: Langer
authors.affiliation: Department of Surgery, Division of General Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Prager
authors.affiliation: Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
mesh_terms: D052242:Adiponectin / Q000172:deficiency / Q000502:physiology*; D000328:Adult; D051397:Aquaglyceroporins / Q000235:genetics* / Q000378:metabolism*; D015992:Body Mass Index; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D056945:Hep G2 Cells; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis / Q000235:genetics; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; D051397:Aquaglyceroporins
keywords: NAFLD; aquaporin; hepatic stellate cells; liver fibrosis; obesity