The 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.

Aldo Grefhorst (1) , Marijke Schreurs , Maaike H. Oosterveer , Victor A. Cortes , Rick Havinga , Andreas W. Herling , Dirk-Jan Reijngoud , Albert K. Groen , Folkert Kuipers

1 UMCG - University Medical Center Groningen [Groningen]

Glycogen storage disease type 1 (GSD-1) is caused by an inherited defect in glucose-6-phosphatase activity, resulting in 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 ~60% reduction of blood glucose, increased hepatic glycogen and triglyceride content, and a markedly enhanced hepatic lipogenic gene expression. In mammals, hepatic expression of lipogenic genes is regulated by the coordinated action of the transcription factors sterol-regulatory element-binding protein-1c (SREBP-1c), liver X receptor α (LXRα) and carbohydrate response element binding protein (ChREBP). Treatment of Lxrα-/- 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.

Mots clés: Life Sciences

Aldo Grefhorst, Marijke Schreurs, Maaike H. Oosterveer, Victor A. Cortes, Rick Havinga, et al.. The 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.. Biochemical Journal, 2010, 432 (2), pp.249-254. ⟨10.1042/BJ20101225⟩. ⟨hal-00535587⟩