Reversal of palmitate-induced impairment of glucose production in the liver is characterised by widespread regulation of lipid metabolism — ASN Events
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  3. Reversal of palmitate-induced impairment of glucose production in the liver is characterised by widespread regulation of lipid metabolism

Reversal of palmitate-induced impairment of glucose production in the liver is characterised by widespread regulation of lipid metabolism (#214)

Brad Hayward 1 , Nicky Konstantopoulos 1 , Kelly Windmill 1 , Andrew Sanigorski 1 , Jacqui Weir 2 , Peter Meikle 2 , Jeremy Jowett 2 , Carsten Schmitz-Peiffer 3 , Juan Molero 1 , Ken Walder 1
  1. Deakin University, Geelong, VIC, Australia
  2. Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
  3. Garvan Institute of Medical Research, Sydney, NSW, Australia

Aims - Obesity-induced insulin resistance of the liver is characterised by increased gluconeogenesis, which contributes to elevated blood glucose levels in individuals with type 2 diabetes.  Using an unbiased approach (global gene expression profiling), we identified biological pathways altered in parallel with restoration of palmitate-induced deregulation of glucose production using metformin and sodium salicylate.

Methods - FAO hepatoma cells were treated with palmitate (0.075mM, 48h) with or without metformin (0.25mM) and sodium salicylate (2mM) in the final 24h of palmitate treatment.  Effects of palmitate, metformin and sodium salicylate on glucose production were determined using the Trinder method, and levels of key insulin signalling proteins measured by immunoblotting.  Microarray analysis followed by gene set enrichment analysis was performed to investigate gene expression levels and pathway regulation.  A lipidomic analysis (HPLC-MS/MS) and in vitro analysis of secreted bile acids and cholesterol were performed.

Results - Reversal of palmitate-induced impairment of glucose production by metformin and sodium salicylate was characterised by down-regulated expression of metabolic pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis.  Total levels of intracellular and secreted cholesterol and bile acids were not different between treatment groups.  Total intracellular levels of diacylgycerol (p=0.043), triacylglycerol (p=0.036) and cholesterol esters (p=0.009) increased with palmitate compared with vehicle; however these were not further altered with metformin and sodium salicylate.  Six individual lipid species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate (p<0.05).

Conclusions - We identified widespread lipid metabolism changes induced by the reversal of palmitate-induced dysregulation of glucose production with metformin and sodium salicylate.  While cholesterol and bile acid levels remained unchanged, the flux through these pathways may in part explain these findings.  The identification of lipid species containing 18:0 and 18:1 side chains being regulated alongside changes to glucose production may indicate potential mediators of glucose production and insulin resistance.