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: Valerio Nobili, Anna Alisi, Renato Cutrera, Guido Carpino, Cristiano De Stefanis, Valentina D'Oria, Rita De Vito, Salvatore Cucchiara, Eugenio Gaudio, Giovanni Musso
• Journal: Thorax (Thorax) Vol. 70 Issue 8 Pg. 769-81 (Aug 2015) ISSN: 1468-3296 [Electronic] England
• PMID: 26069285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Chemical References

• Adiponectin

Topics

• Adiponectin (biosynthesis)
• Apoptosis
• Biopsy
• Body Mass Index
• Cell Cycle
• Child
• Female
• Hepatocytes (pathology)
• Humans
• Liver (metabolism, pathology)
• Male
• Non-alcoholic Fatty Liver Disease (complications, metabolism, pathology)
• Polysomnography
• Retrospective Studies
• Sleep Apnea, Obstructive (complications, metabolism)