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Journal of Lipid Research, Vol. 50, 1374-1383, July 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Reduced insulin-mediated inhibition of VLDL secretion upon pharmacological activation of the liver X receptor in mice

Aldo Grefhorst^1,* and Elizabeth J. Parks^,

^* Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390

This work was supported by a grant from the Ter Meulen Fund, Royal Netherlands Academy of Arts and Science, The Netherlands.

¹ To whom correspondence should be addressed. e-mail: A.Grefhorst{at}med.umcg.nl

The nuclear liver X receptor (LXR) regulates multiple aspects of cholesterol, triacylglycerol (TG), and carbohydrate metabolism. Activation of LXR induces the expression of genes encoding enzymes involved in de novo lipogenesis (DNL) resulting in hepatic steatosis in mice. Pharmacological LXR activation has also been reported to improve insulin sensitivity and glucose homeostasis in diabetic rodents. The effects of pharmacological LXR ligands on insulin's action on hepatic lipid metabolism are not known. We evaluated secretion of VLDL during a hyperinsulinemic euglycemic clamp in mice treated with the LXR-ligand T0901317. In untreated mice, hyperinsulinemia reduced the availability of plasma NEFA for VLDL-TG synthesis, increased the contribution of DNL to VLDL-TG, reduced VLDL particle size, and suppressed overall VLDL-TG production rate by approximately 50%. Upon T0901317 treatment, hyperinsulinemia failed to reduce VLDL particle size or suppress VLDL-TG production rate, but the contribution of DNL to VLDL-TG was increased. In conclusion, the effects of LXR activation by T0901317 on lipid metabolism can override the normal control of insulin to suppress VLDL particle secretion.

Supplementary key words apolipoprotein B • de novo lipogenesis • FoxO1 • LXR • microsomal triglyceride transfer protein • stable isotopes • sterol regulatory element-binding protein-1c • T0901317

Abbreviations: ApoB, apolipoprotein B; DNL, de novo lipogenesis; ER, endoplasmic reticulum; LXR, liver X receptor; MIDA, mass isotopomer distribution analysis; MTP, microsomal triglyceride transfer protein; TG, triacylglycerol

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