Pathways of Acetyl-CoA Metabolism Involved in the Reversal of Palmitate-Induced Glucose Production by Metformin and Salicylate

B. Hayward; J. C. Molero; K. Windmill; A. Sanigorski; J. Weir; N. L. McRae; K. Aston-Mourney; B. Osborne; B. Liao; K. R. Walder; P. J. Meikle; N. Konstantopoulos; C. Schmitz-Peiffer

doi:10.1055/s-0042-111516

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2016; 124(10): 602-612
DOI: 10.1055/s-0042-111516

Article

Pathways of Acetyl-CoA Metabolism Involved in the Reversal of Palmitate-Induced Glucose Production by Metformin and Salicylate

B. Hayward^*

¹School of Medicine – Metabolic Research Unit, Deakin University, Geelong, VIC, Australia

,

J. C. Molero

²Health Innovations Research Institute and School of Health Sciences, RMIT University, Bundoora, VIC, Australia

,

K. Windmill

¹School of Medicine – Metabolic Research Unit, Deakin University, Geelong, VIC, Australia

,

A. Sanigorski

¹School of Medicine – Metabolic Research Unit, Deakin University, Geelong, VIC, Australia

,

J. Weir

³Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia

,

N. L. McRae

¹School of Medicine – Metabolic Research Unit, Deakin University, Geelong, VIC, Australia

,

K. Aston-Mourney

¹School of Medicine – Metabolic Research Unit, Deakin University, Geelong, VIC, Australia

,

B. Osborne

⁴School of Medical Sciences, UNSW Australia

,

B. Liao

⁵Diabetes & Metabolism Division, Garvan Institute of Medical Research and St. Vincent’s Clinical School, UNSW Australia, Sydney, NSW, Australia

,

K. R. Walder

¹School of Medicine – Metabolic Research Unit, Deakin University, Geelong, VIC, Australia

,

P. J. Meikle

³Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia

,

N. Konstantopoulos^**

¹School of Medicine – Metabolic Research Unit, Deakin University, Geelong, VIC, Australia

,

C. Schmitz-Peiffer

⁵Diabetes & Metabolism Division, Garvan Institute of Medical Research and St. Vincent’s Clinical School, UNSW Australia, Sydney, NSW, Australia

› Author Affiliations

Abstract

The pathways through which fatty acids induce insulin resistance have been the subject of much research. We hypothesise that by focussing on the reversal of insulin resistance, novel insights can be made regarding the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered during the prevention of palmitate-induced glucose production in hepatocytes using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075 mM, 48 h) with or without metformin (0.25 mM) and sodium salicylate (2 mM) in the final 24 h of palmitate treatment, and effects on glucose production were determined. RNA microarray measurements followed by gene set enrichment analysis were performed to investigate pathway regulation. Lipidomic analysis and measurement of secreted bile acids and cholesterol were also performed. Reversal of palmitate-induced glucose production by metformin and sodium salicylate was characterised by co-ordinated down-regulated expression of pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. All 20 enzymes that regulate the conversion of acetyl-CoA to cholesterol were reduced following metformin and sodium salicylate. Selected findings were confirmed using primary mouse hepatocytes. Although total intracellular levels of diacylglycerol, triacylglycerol and cholesterol esters increased with palmitate, these were not, however, further altered by metformin and sodium salicylate. 6 individual diacylglycerol, triacylglycerol and cholesterol ester species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate. These results implicate acetyl-CoA metabolism and C18 lipid species as modulators of hepatic glucose production that could be targeted to improve glucose homeostasis.

Key words

insulin resistance - liver - gene expression microarray - lipidomics

Full Text

References

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