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J. Biol. Chem., Vol. 283, Issue 37, 25437-25445, September 12, 2008

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Lxr Deficiency Hampers the Hepatic Adaptive Response to Fasting in Mice^*

Maaike H. Oosterveer¹, Theo H. van Dijk, Aldo Grefhorst, Vincent W. Bloks, Rick Havinga, Folkert Kuipers, and Dirk-Jan Reijngoud

From the Departments of Pediatrics and Laboratory Medicine, Center for Liver Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, P. O. Box 30.001, Groningen 9700 RB, The Netherlands

Besides its well established role in control of cellular cholesterol homeostasis, the liver X receptor (LXR) has been implicated in the regulation of hepatic gluconeogenesis. We investigated the role of the major hepatic LXR isoform in hepatic glucose metabolism during the feeding-to-fasting transition in vivo. In addition, we explored hepatic glucose sensing by LXR during carbohydrate refeeding. Lxr^-/- mice and their wild-type littermates were subjected to a fasting-refeeding protocol and hepatic carbohydrate fluxes as well as whole body insulin sensitivity were determined in vivo by stable isotope procedures. Lxr^-/- mice showed an impaired response to fasting in terms of hepatic glycogen depletion and triglyceride accumulation. Hepatic glucose 6-phosphate turnover was reduced in 9-h fasted Lxr^-/- mice as compared with controls. Although hepatic gluconeogenic gene expression was increased in 9-h fasted Lxr^-/- mice compared with wild-type controls, the actual gluconeogenic flux was not affected by Lxr deficiency. Hepatic and peripheral insulin sensitivity were similar in Lxr^-/- and wild-type mice. Compared with wild-type controls, the induction of hepatic lipogenic gene expression was blunted in carbohydrate-refed Lxr^-/- mice, which was associated with lower plasma triglyceride concentrations. Yet, expression of "classic" LXR target genes Abca1, Abcg5, and Abcg8 was not affected by Lxr deficiency in carbohydrate-refed mice. In summary, these studies identify LXR as a physiologically relevant mediator of the hepatic response to fasting. However, the data do not support a role for LXR in hepatic glucose sensing.

Received for publication, March 10, 2008 , and in revised form, July 8, 2008.

^* This work was supported by the Dutch Diabetes Foundation (Grant 2002.00.041). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table S1.

¹ To whom correspondence should be addressed. Tel.: 31-50-361-1409; Fax: 31-50-361-1732; E-mail: M.H.Oosterveer{at}med.umcg.nl.

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