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Originally published In Press as doi:10.1194/jlr.M600170-JLR200 on November 4, 2006

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Journal of Lipid Research, Vol. 48, 337-347, February 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Cholesterol feeding strongly reduces hepatic VLDL-triglyceride production in mice lacking the liver X receptor {alpha}boxs

Jelske N. van der Veen1,*, Rick Havinga*, Vincent W. Bloks*, Albert K. Groen{dagger} and Folkert Kuipers*

* Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands
{dagger} Department of Medical Biochemistry, University of Amsterdam, Amsterdam, The Netherlands

boxs The online version of this article (available at http://www.jlr.org) contains additional figure.

Published, JLR Papers in Press, November 4, 2006.

1 To whom correspondence should be addressed. e-mail: j.n.van.der.veen{at}med.umcg.nl

The oxysterol-activated nuclear receptor liver X receptor {alpha} (LXR{alpha}) has been implicated in the control of both cholesterol and fatty acid metabolism. In this study, we have evaluated the effects of excess dietary cholesterol on hepatic cholesterol metabolism, lipogenesis, and VLDL production in homozygous (Lxr{alpha}–/–), heterozygous (Lxr{alpha}+/–), and wild-type mice. Mice were fed either chow or a cholesterol-enriched diet (1%, w/w) for 2 weeks. On the high-cholesterol diet, fractional cholesterol absorption was higher in Lxr{alpha}–/– mice than in controls, leading to delivery of more dietary cholesterol to the liver. Lxr{alpha}–/– mice were not able to induce expression of hepatic Abcg5/Abcg8, and massive accumulation of free cholesterol and cholesteryl esters (CEs) occurred. Interestingly, despite the inability to upregulate Abcg5/Abcg8, the highly increased hepatic free cholesterol content did stimulate biliary cholesterol output in Lxr{alpha}–/– mice. Hepatic cholesterol accumulation was accompanied by decreased hepatic expression of lipogenic genes, probably caused by impaired sterol-regulatory element binding protein 1c processing, lower hepatic triglyceride (TG) contents, strongly reduced plasma TG concentrations (–90%), and reduced VLDL-TG production rates (–60%) in Lxr{alpha}–/– mice. VLDL particles were smaller and CE-enriched under these conditions. Lxr{alpha} deficiency did not affect VLDL formation under chow-fed conditions. Hepatic stearyl coenzyme A desaturase 1 expression was decreased dramatically in Lxr{alpha}–/– mice and did not respond to cholesterol feeding, but fatty acid profiles of liver and VLDL were only slightly different between Lxr{alpha}–/– and wild-type mice. Our data indicate that displacement of TGs by CEs during the VLDL assembly process underlies hypotriglyceridemia in cholesterol-fed Lxr{alpha}–/– mice.

Supplementary key words nuclear receptors • cholesterol absorption • ATP binding cassette transporter g5 • ATP binding cassette transporter g8 • biliary cholesterol secretion • lipogenesis • fatty acids • very low density lipoprotein

Abbreviations: Acc-1, acetyl-coenzyme A carboxylase 1; CE, cholesteryl ester; Cyp7A1, cholesterol 7{alpha}-hydroxylase; ER, endoplasmic reticulum; Gpat, glycerol-3-phosphate acyltransferase; Hmgr, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; LXR, liver X receptor; PL, phospholipid; SCAP, sterol-regulatory element binding protein cleavage-activating protein; Scd1, stearyl coenzyme A desaturase 1; Srebp-1c, sterol-regulatory element binding protein 1c; TG, triglyceride


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