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

Autor:	Hayward B; School of Medicine - Metabolic Research Unit, Deakin University, Geelong, VIC, Australia., Molero JC; Health Innovations Research Institute and School of Health Sciences, RMIT University, Bundoora, VIC, Australia., Windmill K; School of Medicine - Metabolic Research Unit, Deakin University, Geelong, VIC, Australia., Sanigorski A; School of Medicine - Metabolic Research Unit, Deakin University, Geelong, VIC, Australia., Weir J; Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia., McRae NL; School of Medicine - Metabolic Research Unit, Deakin University, Geelong, VIC, Australia., Aston-Mourney K; School of Medicine - Metabolic Research Unit, Deakin University, Geelong, VIC, Australia., Osborne B; School of Medical Sciences, UNSW Australia., Liao B; Diabetes & Metabolism Division, Garvan Institute of Medical Research and St. Vincent's Clinical School, UNSW Australia, Sydney, NSW, Australia., Walder KR; School of Medicine - Metabolic Research Unit, Deakin University, Geelong, VIC, Australia., Meikle PJ; Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia., Konstantopoulos N; School of Medicine - Metabolic Research Unit, Deakin University, Geelong, VIC, Australia., Schmitz-Peiffer C; Diabetes & Metabolism Division, Garvan Institute of Medical Research and St. Vincent's Clinical School, UNSW Australia, Sydney, NSW, Australia.
Jazyk:	angličtina
Zdroj:	Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association [Exp Clin Endocrinol Diabetes] 2016; Vol. 124 (10), pp. 602-612. Date of Electronic Publication: 2016 Sep 29.
DOI:	10.1055/s-0042-111516
Abstrakt:	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. (© Georg Thieme Verlag KG Stuttgart · New York.)
Databáze:	MEDLINE
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