Identification of secreted factors linking hepatic steatosis to insulin resistance. — ASN Events
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  2. ADS Basic Orals: Lipids, Cytokines and Glucose Tolerance
  3. Identification of secreted factors linking hepatic steatosis to insulin resistance.

Identification of secreted factors linking hepatic steatosis to insulin resistance. (#192)

Ruth Meex 1 , Andrew Hoy 1 , Alexander Morris 1 , Russell Brown 1 , Jennifer Lo 1 , Melissa Burke 1 , Robert Goode 1 , Bronwyn Kingwell 2 , Michael Kraakman 2 , Mark Febbraio 2 , Jan Willem Greve 3 , Sander Rensen 3 , Mark Molloy 4 , Graeme Lancaster 2 , Clinton Bruce 1 , Matthew Watt 1
  1. Monash University, Clayton, VIC, Australia
  2. Baker IDI Heart and Diabetes Institute , Melbourne, Victoria, Australia
  3. Maastricht University, Maastricht, the Netherlands
  4. Macquarie University, Sydney, NSW, Australia

Non-alcoholic fatty liver disease (NAFLD) is a common health problem that is associated with obesity. Liver steatosis is an early manifestation in the aetiology of NAFLD, which usually precedes the development type 2 diabetes. We tested the hypothesis that protein and lipid signals originating from the fatty hepatocyte induce ‘cross-talk’ with other tissues to modulate metabolic phenotypes.

Male C57Bl/6J mice were fed a chow diet (Chow) or high-fat diet (HFD) for 6-8 weeks to induce simple steatosis. Hepatocytes were isolated and cultured, and the secreted products were collected in protein and lipid free media for analysis (=conditioned media, CM).

HFD CM but not Chow CM induced insulin resistance and inflammation in cultured cells.  Quantitative analysis of the CM detected 17 lipid classes and >200 lipid species, and showed increased secretion of 11 lipid classes in HFD CM compared with Chow CM (including cholesterol esters, ceramides, diacylglycerols, phosphatidylcholine and triacylglycerol). Isobaric tag for relative and absolute (iTRAQ) labelling and mass spectrometry quantification of the CM detected 538 proteins. Of these proteins, 115 were identified as ‘classically secreted’, 31 of which were upregulated, and three that were downregulated in HFD CM. Fetuin B was increased in the CM of HFD hepatocytes and subsequent studies showed that fetuin B was elevated in patients with liver steatosis compared with weight-matched patients without steatosis, and fetuin B correlated with insulin resistance. Further studies in lean mice showed that acute injection of fetuin B decreased glucose tolerance, whereas adeno-associated virus administration of fetuin B shRNA in obese mice reduced plasma fetuin B by 33% and improved glucose tolerance.

Hepatic steatosis invokes changes in the protein and lipid secretory profile that in turn causes inflammation and insulin resistance, and targeted profiling identified fetuin B as a steatosis responsive protein that was shown to cause glucose intolerance. Further interrogation of the secreted proteins may be a useful strategy for understanding the development of impaired glucose metabolism.