Lxralpha deficiency hampers the hepatic adaptive response to fasting in mice.
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. Lxralpha(-/-) 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. Lxralpha(-/-) 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 Lxralpha(-/-) mice as compared with controls. Although hepatic gluconeogenic gene expression was increased in 9-h fasted Lxralpha(-/-) mice compared with wild-type controls, the actual gluconeogenic flux was not affected by Lxralpha deficiency. Hepatic and peripheral insulin sensitivity were similar in Lxralpha(-/-) and wild-type mice. Compared with wild-type controls, the induction of hepatic lipogenic gene expression was blunted in carbohydrate-refed Lxralpha(-/-) mice, which was associated with lower plasma triglyceride concentrations. Yet, expression of "classic" LXR target genes Abca1, Abcg5, and Abcg8 was not affected by Lxralpha deficiency in carbohydrate-refed mice. In summary, these studies identify LXRalpha 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.
Oosterveer
Maaike H
MH
Department of Pediatrics, Groningen 9700 RB, The Netherlands. Electronic address: M.H.Oosterveer@med.umcg.nl.
van Dijk
Theo H
TH
Department of Pediatrics, Groningen 9700 RB, The Netherlands; 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.
Grefhorst
Aldo
A
Department of Pediatrics, Groningen 9700 RB, The Netherlands.
Bloks
Vincent W
VW
Department of Pediatrics, Groningen 9700 RB, The Netherlands.
Havinga
Rick
R
Department of Pediatrics, Groningen 9700 RB, The Netherlands.
Kuipers
Folkert
F
Department of Pediatrics, Groningen 9700 RB, The Netherlands.
Reijngoud
Dirk-Jan
DJ
Department of Pediatrics, Groningen 9700 RB, The Netherlands; 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.
D000818:Animals; D002241:Carbohydrates / Q000737:chemistry; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005508:Food Deprivation; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006019:Glycolysis; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D002241:Carbohydrates; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D019298:Glucose-6-Phosphate; D002784:Cholesterol; D005947:Glucose