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; Marijke Schreurs; Maaike H Oosterveer; Victor A Cortés; Rick Havinga; Andreas W Herling; Dirk-Jan Reijngoud; Albert K Groen; Folkert Kuipers

doi:10.1042/BJ20101225

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

Biochem J. 2010 Dec 1;432(2):249-54. doi: 10.1042/BJ20101225.

Authors

Aldo Grefhorst¹, Marijke Schreurs, Maaike H Oosterveer, Victor A Cortés, Rick Havinga, Andreas W Herling, Dirk-Jan Reijngoud, Albert K Groen, Folkert Kuipers

Affiliation

¹ Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. a.grefhorst@med.umcg.nl

PMID: 20854262
DOI: 10.1042/BJ20101225

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cholesterol / metabolism
Disease Models, Animal
Gene Expression Regulation*
Glucose-6-Phosphatase / adverse effects
Glucose-6-Phosphatase / genetics
Glucose-6-Phosphatase / metabolism
Glycogen Storage Disease / enzymology
Glycogen Storage Disease / genetics*
Glycogen Storage Disease / metabolism
Humans
Imidazoles / administration & dosage
Imidazoles / pharmacology
Liver / enzymology
Liver / metabolism
Liver Glycogen / metabolism
Liver X Receptors
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins / deficiency*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Orphan Nuclear Receptors / deficiency
Orphan Nuclear Receptors / genetics
Orphan Nuclear Receptors / metabolism
Pyridines / administration & dosage
Pyridines / pharmacology
RNA / genetics
RNA / isolation & purification
Transcription Factors / deficiency*
Transcription Factors / genetics
Transcription Factors / metabolism
Triglycerides / metabolism

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Imidazoles
Liver Glycogen
Liver X Receptors
Mlxipl protein, mouse
NR1H3 protein, human
Nr1h3 protein, mouse
Nuclear Proteins
Orphan Nuclear Receptors
Pyridines
S 4048
Transcription Factors
Triglycerides
RNA
Cholesterol
Glucose-6-Phosphatase