s-4048 and Glycogen-Storage-Disease

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.

Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cholesterol; Disease Models, Animal; Gene Expression Regulation; Glucose-6-Phosphatase; Glycogen Storage Disease; Humans; Imidazoles; Liver; Liver Glycogen; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; Orphan Nuclear Receptors; Pyridines; RNA; Transcription Factors; Triglycerides