title: LRH-1-dependent glucose sensing determines intermediary metabolism in liver.
abstract: Liver receptor homolog 1 (LRH-1), an established regulator of cholesterol and bile acid homeostasis, has recently emerged as a potential drug target for liver disease. Although LRH-1 activation may protect the liver against diet-induced steatosis and insulin resistance, little is known about how LRH-1 controls hepatic glucose and fatty acid metabolism under physiological conditions. We therefore assessed the role of LRH-1 in hepatic intermediary metabolism. In mice with conditional deletion of Lrh1 in liver, analysis of hepatic glucose fluxes revealed reduced glucokinase (GCK) and glycogen synthase fluxes as compared with those of wild-type littermates. These changes were attributed to direct transcriptional regulation of Gck by LRH-1. Impaired glucokinase-mediated glucose phosphorylation in LRH-1-deficient livers was also associated with reduced glycogen synthesis, glycolysis, and de novo lipogenesis in response to acute and prolonged glucose exposure. Accordingly, hepatic carbohydrate response element-binding protein activity was reduced in these animals. Cumulatively, these data identify LRH-1 as a key regulatory component of the hepatic glucose-sensing system required for proper integration of postprandial glucose and lipid metabolism.
authors: Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors: Maaike H
authors: MH
authors: Oosterveer
authors: Chikage
authors: C
authors: Mataki
authors: Hiroyasu
authors: H
authors: Yamamoto
authors: Taoufiq
authors: T
authors: Harach
authors: Norman
authors: N
authors: Moullan
authors: Theo H
authors: TH
authors: van Dijk
authors: Eduard
authors: E
authors: Ayuso
authors: Fatima
authors: F
authors: Bosch
authors: Catherine
authors: C
authors: Postic
authors: Albert K
authors: AK
authors: Groen
authors: Johan
authors: J
authors: Auwerx
authors: Kristina
authors: K
authors: Schoonjans
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D006019:Glycolysis; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D008112:Liver Glycogen; C506001:Mlxipl protein, mouse; C431936:Nr5a2 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D006006:Glycogen Synthase; D005941:Glucokinase; D005947:Glucose