title: Carbohydrate-response-element-binding protein (ChREBP) and not the liver X receptor α (LXRα) mediates elevated hepatic lipogenic gene expression in a mouse model of glycogen storage disease type 1.
abstract: GSD-1 (glycogen storage disease type 1) is caused by an inherited defect in glucose-6-phosphatase activity, resulting in a massive accumulation of hepatic glycogen content and an induction of de novo lipogenesis. The chlorogenic acid derivative S4048 is a pharmacological inhibitor of the glucose 6-phosphate transporter, which is part of glucose-6-phosphatase, and allows for mechanistic studies concerning metabolic defects in GSD-1. Treatment of mice with S4048 resulted in an ~60% reduction in blood glucose, increased hepatic glycogen and triacylglycerol (triglyceride) content, and a markedly enhanced hepatic lipogenic gene expression. In mammals, hepatic expression of lipogenic genes is regulated by the co-ordinated action of the transcription factors SREBP (sterol-regulatory-element-binding protein)-1c, LXRα (liver X receptor α) and ChREBP (carbohydrate-response-element-binding protein). Treatment of Lxra-/- mice and Chrebp-/- mice with S4048 demonstrated that ChREBP, but not LXRα, mediates the induction of hepatic lipogenic gene expression in this murine model of GSD-1. Thus ChREBP is an attractive target to alleviate derangements in lipid metabolism observed in patients with GSD-1.
authors.affiliation: Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. a.grefhorst@med.umcg.nl
authors.forename: Aldo
authors.initials: A
authors.lastname: Grefhorst
authors.forename: Marijke
authors.initials: M
authors.lastname: Schreurs
authors.forename: Maaike H
authors.initials: MH
authors.lastname: Oosterveer
authors.forename: Victor A
authors.initials: VA
authors.lastname: Cortés
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Herling
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Reijngoud
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005952:Glucose-6-Phosphatase / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D006008:Glycogen Storage Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D007093:Imidazoles; D008112:Liver Glycogen; D000071518:Liver X Receptors; C506001:Mlxipl protein, mouse; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D011725:Pyridines; C403582:S 4048; D014157:Transcription Factors; D014280:Triglycerides; D012313:RNA; D002784:Cholesterol; D005952:Glucose-6-Phosphatase