Lxrα Deficiency Hampers the Hepatic Adaptive Response to Fasting in Mice
Copyright policy )Lxrα 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.
- University of Groningen Netherlands
- University Medical Center Groningen Netherlands
- University Medical Center Groningen Netherlands
- Amsterdam UMC Netherlands
LIVER, Time Factors, Carbohydrates, NUCLEAR RECEPTOR LXR, Glucose-6-Phosphate, Receptors, Cytoplasmic and Nuclear, METABOLISM, GLYCOGEN, OB/OB MICE, Models, Biological, GLUCOSE, ACTIVATION, Mice, Animals, DE-NOVO SYNTHESIS, Triglycerides, Liver X Receptors, X-RECEPTOR, Orphan Nuclear Receptors, GENE, DNA-Binding Proteins, Mice, Inbred C57BL, Cholesterol, Glucose, Gene Expression Regulation, Liver, Food Deprivation, Glycolysis
LIVER, Time Factors, Carbohydrates, NUCLEAR RECEPTOR LXR, Glucose-6-Phosphate, Receptors, Cytoplasmic and Nuclear, METABOLISM, GLYCOGEN, OB/OB MICE, Models, Biological, GLUCOSE, ACTIVATION, Mice, Animals, DE-NOVO SYNTHESIS, Triglycerides, Liver X Receptors, X-RECEPTOR, Orphan Nuclear Receptors, GENE, DNA-Binding Proteins, Mice, Inbred C57BL, Cholesterol, Glucose, Gene Expression Regulation, Liver, Food Deprivation, Glycolysis
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