Interrelationship between Liver X Receptor alpha, Sterol Regulatory Element-binding Protein-1c, Peroxisome Proliferator-activated Receptor gamma, and Small Heterodimer Partner in the Transcriptional Regulation of Glucokinase Gene Expression in Liver

Abstract

Liver glucokinase (LGK) plays an essential role in controlling blood glucose levels and maintaining cellular metabolic functions. Expression of LGK is induced mainly regulated by insulin through sterol regulatory element-binding protein-1c (SREBP-1c) as a mediator. Since LGK expression is known to be decreased in the liver of liver X receptor (LXR) knockout mice, we have investigated whether LGK might be directly activated by LXR alpha. Furthermore, we have studied interrelationship between transcription factors that control gene expression of LGK. In the current studies, we demonstrated that LXR alpha increased LGK expression in primary hepatocytes and that there is a functional LXR response element in the LGK gene promoter as shown by electrophoretic mobility shift and chromatin precipitation assay. In addition, our studies demonstrate that LXR alpha and insulin activation of the LGK gene promoter occurs through a multifaceted indirect mechanism. LXR alpha increases SREBP-1c expression and then insulin stimulates the processing of the membrane-bound precursor SREBP-1c protein, and it activates LGK expression through SREBP sites in its promoter. LXR alpha also activates the LGK promoter by increasing the transcriptional activity and induction of peroxisome proliferator-activated receptor (PPAR)-gamma, which also stimulates LGK expression through a peroxisome proliferator-responsive element. This activation is tempered through a negative mechanism, where a small heterodimer partner (SHP) decreases LGK gene expression by inhibiting the transcriptional activity of LXR alpha and PPAR gamma by directly interacting with their common heterodimer partner RXR alpha. From these data, we propose a mechanism for LXR alpha in controlling the gene expression of LGK that involves activation through SREBP-1c and PPAR gamma and inhibition through SHP.