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Pathways of acetyl-CoA metabolism involved in the reversal of palmitate-induced glucose production by metformin and salicylate

Hayward, B., Molero, J., Windmill, K., Sanigorski, A., Weir, J., McRae, N., Aston-Mourney, K., Osborne, B., Liao, B., Walder, K.R., Meikle, P.J., Konstantopoulos, N. and Schmitz-Peiffer, C. 2016, Pathways of acetyl-CoA metabolism involved in the reversal of palmitate-induced glucose production by metformin and salicylate, Experimental and clinical endocrinology and diabetes, vol. 124, no. 10, pp. 602-612, doi: 10.1055/s-0042-111516.

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Title Pathways of acetyl-CoA metabolism involved in the reversal of palmitate-induced glucose production by metformin and salicylate
Author(s) Hayward, B.
Molero, J.
Windmill, K.
Sanigorski, A.
Weir, J.
McRae, N.
Aston-Mourney, K.
Osborne, B.
Liao, B.
Walder, K.R.
Meikle, P.J.
Konstantopoulos, N.
Schmitz-Peiffer, C.
Journal name Experimental and clinical endocrinology and diabetes
Volume number 124
Issue number 10
Start page 602
End page 612
Total pages 11
Publisher Thieme
Place of publication Munich, Germany
Publication date 2016
ISSN 1439-3646
Keyword(s) insulin resistance
liver
gene expression microarray
lipidomics
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
HEPATIC INSULIN-RESISTANCE
PROTEIN-KINASE-C
SKELETAL-MUSCLE CELLS
NF-KAPPA-B
FATTY-ACIDS
IKK-BETA
MICE
ACTIVATION
DIACYLGLYCEROL
Summary 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.
Language eng
DOI 10.1055/s-0042-111516
Field of Research 110306 Endocrinology
1103 Clinical Sciences
Socio Economic Objective 920104 Diabetes
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, J.A. Barth Verlag
Persistent URL http://hdl.handle.net/10536/DRO/DU:30088875

Document type: Journal Article
Collection: School of Medicine
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