Farnesoid X receptor induces GLUT4 expression through FXR response element in the GLUT4 promoter

Hong Shen; Yu Zhang; Hong Ding; Xu Wang; Lili Chen; Hualiang Jiang; Xu Shen

doi:10.1159/000149779

Farnesoid X receptor induces GLUT4 expression through FXR response element in the GLUT4 promoter

Cell Physiol Biochem. 2008;22(1-4):1-14. doi: 10.1159/000149779. Epub 2008 Jul 25.

Authors

Hong Shen¹, Yu Zhang, Hong Ding, Xu Wang, Lili Chen, Hualiang Jiang, Xu Shen

Affiliation

¹ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.

PMID: 18769028
DOI: 10.1159/000149779

Abstract

GLUT4, the main insulin-responsive glucose transporter, plays a critical role in maintaining systemic glucose homeostasis and is subject to complicated metabolic regulation. GLUT4 expression disorder might cause insulin resistance, and over-expression of GLUT4 has been confirmed to ameliorate diabetes. Here, we reported that farnesoid X receptor (FXR) and its agonist chenodeoxycholic acid (CDCA) could induce GLUT4 transcription in 3T3-L1 and HepG2 cells. Furthermore, CDCA could increase the GLUT4 protein amount in C57BL/6J mice sex-dependently. The following progressive 5'-deletion analysis and site-mutation investigation further suggested that FXR could induce GLUT4 expression through FXR response element (FXRE) in the GLUT4 promoter. EMSA and knock-down of retinoid X receptor (RXR) indicated that FXR binds to the GLUT4-FXRE as a monomer and RXR does not participate in the FXR stimulation of GLUT4 expression. In addition, we demonstrated that FXR does not interfere with insulin-induced GLUT4 translocation to plasma membrane. All these data thereby implied that FXR is a new transcription factor of GLUT4, further elucidating the potential role for FXR in glucose metabolism.

Publication types

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

MeSH terms

3T3-L1 Cells
Animals
Base Sequence
Binding Sites
Cell Line, Tumor
Cell Membrane / drug effects
Cell Membrane / metabolism
Chenodeoxycholic Acid / pharmacology
DNA-Binding Proteins / agonists
DNA-Binding Proteins / chemistry
DNA-Binding Proteins / metabolism*
Electrophoretic Mobility Shift Assay
Female
Gene Expression Regulation / drug effects
Glucose Transporter Type 4 / genetics*
Glucose Transporter Type 4 / metabolism
Humans
Insulin / pharmacology
Male
Mice
Mice, Inbred C57BL
Molecular Sequence Data
PPAR gamma / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Protein Binding / drug effects
Protein Conformation
Protein Transport / drug effects
Receptors, Cytoplasmic and Nuclear / agonists
Receptors, Cytoplasmic and Nuclear / chemistry
Receptors, Cytoplasmic and Nuclear / metabolism*
Response Elements / genetics*
Retinoid X Receptors / metabolism
Sex Characteristics
Transcription Factors / agonists
Transcription Factors / chemistry
Transcription Factors / metabolism*

Substances

DNA-Binding Proteins
Glucose Transporter Type 4
Insulin
PPAR gamma
Receptors, Cytoplasmic and Nuclear
Retinoid X Receptors
Transcription Factors
farnesoid X-activated receptor
Chenodeoxycholic Acid
Phosphatidylinositol 3-Kinases