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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

Authors
 Tae-Hyun Kim  ;  Hail Kim  ;  Joo-Man Park  ;  Seung-Soon Im  ;  Jin-Sik Bae  ;  Mi-Young Kim  ;  Ho-Geun Yoon  ;  Ji-Young Cha  ;  Kyung-Sup Kim  ;  Yong-Ho Ahn 
Citation
 JOURNAL OF BIOLOGICAL CHEMISTRY, Vol.284(22) : 15071-15083, 2009 
Journal Title
 JOURNAL OF BIOLOGICAL CHEMISTRY 
ISSN
 0021-9258 
Issue Date
2009
MeSH
Animals ; Base Sequence ; Cell Line ; DNA-Binding Proteins/metabolism* ; Gene Expression Regulation, Enzymologic* ; Glucokinase/genetics* ; Glucokinase/metabolism ; Hepatocytes/enzymology ; Humans ; Liver/enzymology* ; Liver X Receptors ; Mice ; Models, Biological ; Molecular Sequence Data ; Orphan Nuclear Receptors ; PPAR gamma/genetics ; PPAR gamma/metabolism* ; Protein Binding ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Receptors, Cytoplasmic and Nuclear/metabolism* ; Response Elements/genetics ; Sterol Regulatory Element Binding Protein 1/metabolism* ; Transcription, Genetic
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 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
Files in This Item:
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DOI
10.1074/jbc.M109.006742
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Sup(김경섭) ORCID logo https://orcid.org/0000-0001-8483-8537
Kim, Mi Young(김미영)
Kim, Tae Hyun(김태현)
Kim, Ha Il(김하일)
Park, Joo Man(박주만)
Bae, Jin Sik(배진식)
Ahn, Yong Ho(안용호) ORCID logo https://orcid.org/0000-0002-4133-0757
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
Im, Seung Soon(임승순)
Cha, Ji Young(차지영)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/103892
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