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.
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 LXRalpha. Furthermore, we have studied interrelationship between transcription factors that control gene expression of LGK. In the current studies, we demonstrated that LXRalpha 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 LXRalpha and insulin activation of the LGK gene promoter occurs through a multifaceted indirect mechanism. LXRalpha 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. LXRalpha 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 LXRalpha and PPARgamma by directly interacting with their common heterodimer partner RXRalpha. From these data, we propose a mechanism for LXRalpha in controlling the gene expression of LGK that involves activation through SREBP-1c and PPARgamma and inhibition through SHP.
Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Sciences, Center for Chronic Metabolic Disease Research, and Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Tae-Hyun
TH
Kim
Hail
H
Kim
Joo-Man
JM
Park
Seung-Soon
SS
Im
Jin-Sik
JS
Bae
Mi-Young
MY
Kim
Ho-Geun
HG
Yoon
Ji-Young
JY
Cha
Kyung-Sup
KS
Kim
Yong-Ho
YH
Ahn
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000201:enzymology*; D000071518:Liver X Receptors; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; C099713:nuclear receptor subfamily 0, group B, member 2; D005941:Glucokinase