Liver X receptor antagonist reduces lipid formation and increases glucose metabolism in myotubes from lean, obese and type 2 diabetic individuals.
OBJECTIVE
Liver X receptors (LXRs) play important roles in lipid and carbohydrate metabolism. The purpose of the present study was to evaluate effects of the endogenous LXR agonist 22-R-hydroxycholesterol (22-R-HC) and its stereoisomer 22-S-hydroxycholesterol (22-S-HC), in comparison with the synthetic agonist T0901317 on lipid and glucose metabolism in human skeletal muscle cells (myotubes).


METHODS
Myotubes established from lean and obese control volunteers and from obese type 2 diabetic volunteers were treated with LXR ligands for 4 days. Lipid and glucose metabolisms were studied with labelled precursors, and gene expression was analysed using real-time PCR.


RESULTS
Treatment with T0901317 increased lipogenesis (de novo lipid synthesis) and lipid accumulation in myotubes, this increase being more pronounced in myotubes from type 2 diabetic volunteers than from lean volunteers. Furthermore, 22-S-HC efficiently counteracted the T0901317-induced enhancement of lipid formation. Moreover, synthesis of diacylglycerol, cholesteryl ester and free cholesterol from acetate was reduced below baseline by 22-S-HC, whereas glucose uptake and oxidation were increased. Both 22-S-HC and 22-R-HC, in contrast to T0901317, decreased the expression of genes involved in cholesterol synthesis, whereas only 22-R-HC, like T0901317, increased the expression of the gene encoding the reverse cholesterol transporter ATP-binding cassette subfamily A1 (ABCA1).


CONCLUSIONS
T0901317-induced lipogenesis and lipid formation was more pronounced in myotubes from type 2 diabetic patients than from lean individuals. 22-S-HC counteracted these effects and reduced de novo lipogenesis below baseline, while glucose uptake and oxidation were increased.
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, Oslo, 0316, Norway.
E T
ET
Kase
G H
GH
Thoresen
S
S
Westerlund
K
K
Højlund
A C
AC
Rustan
M
M
Gaster
D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000502:physiology*; D000071518:Liver X Receptors; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D013851:Thinness / Q000097:blood
D001786:Blood Glucose; D004268:DNA-Binding Proteins; D005947:Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear