title: Altered gut-liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver.
abstract: BACKGROUND
  Mechanism(s) connecting obstructive sleep apnoea syndrome (OSAS) to liver injury in paediatric non-alcoholic fatty liver disease (NAFLD) are unknown. We hypothesised alterations in gut-liver axis and in the pool and phenotype of hepatic progenitor cells (HPCs) may be involved in OSAS-associated liver injury in NAFLD.
  
  
  METHODS
  Eighty biopsy-proven NAFLD children (age, mean±SD, 11.4±2.0 years, 56% males, body mass index z-score 1.95±0.57) underwent a clinical-biochemical assessment, with measurement of insulin sensitivity, plasma cytokines, lipopolysaccharide (LPS), an intestinal permeability test and a standard polysomnography. Hepatic toll-like receptor (TLR)-4 expression by liver-resident cells and overall number and expression of resistin and adiponectin by HPCs were assessed by immunofluorescence and immunohistochemistry. OSAS was defined by an apnoea/hypopnoea index ≥1.
  
  
  RESULTS
  OSAS was characterised by an increased intestinal permeability and endotoxemia, coupled with TLR-4 upregulation in hepatocytes, Kupffer and hepatic stellate cells (HSCs) and by an expansion of an adiponectin-deficient HPC pool, key features of steatohepatitis and fibrosis.The duration of haemoglobin desaturation (SaO2 <90%) independently predicted intestinal permeability (β: 0.396; p=0.026), plasma LPS (β: 0.358; p=0.008) and TLR-4 expression by hepatocytes (β: 0.332; p=0.009), Kupffer cells (β: 0.357; p=0.006) and HSCs (β:0.445; p=0.002).SaO2 <90% predicted also HPC number (β: 0.471; p=0.001) and impaired adiponectin expression by HPC pool (β: -0.532; p=0.0009).These relationships were observed in obese and non-obese children.
  
  
  CONCLUSIONS
  In paediatric NAFLD, OSAS is associated with increased endotoxemia coupled with impaired gut barrier function, with increased TLR-4-mediated hepatic susceptibility to endotoxemia and with an expansion of an adiponectin-deficient HPC pool. These alterations may represent a novel pathogenic link and a potential therapeutic target for OSAS-associated liver injury in NAFLD.
authors.affiliation: Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Alisi
authors.affiliation: Pneumology Unit-Sleep and NIV Laboratory, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Cutrera
authors.affiliation: Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: De Stefanis
authors.affiliation: Confocal Microscopy Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Oria
authors.affiliation: Pathology Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: De Vito
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cucchiara
authors.affiliation: Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University, Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Gradenigo Hospital C.so Regina Margherita 8, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Musso
mesh_terms: D052242:Adiponectin / Q000096:biosynthesis*; D017209:Apoptosis; D001706:Biopsy; D015992:Body Mass Index; D002453:Cell Cycle; D002648:Child; D005260:Female; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D017286:Polysomnography; D012189:Retrospective Studies; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000378:metabolism*
chemical_list: D052242:Adiponectin
keywords: Sleep apnoea