Zinc Finger Protein 407 (ZFP407) Regulates Insulin-stimulated Glucose Uptake and Glucose Transporter 4 (Glut4) mRNA*

Background: Glucose uptake in adipocytes is largely mediated by GLUT4 and is impaired in type 2 diabetics. Results: ZFP407 regulates expression of GLUT4 and other peroxisome proliferator-activated receptor γ target genes. Conclusion: ZFP407 regulates insulin-stimulated glucose uptake by altering the levels of GLUT4. Significance: ZFP407 represents a new therapeutic target for type 2 diabetes. The glucose transporter GLUT4 facilitates insulin-stimulated glucose uptake in peripheral tissues including adipose, muscle, and heart. GLUT4 function is impaired in obesity and type 2 diabetes leading to hyperglycemia and an increased risk of cardiovascular disease and neuropathy. To better understand the regulation of GLUT4 function, a targeted siRNA screen was performed and led to the discovery that ZFP407 regulates insulin-stimulated glucose uptake in adipocytes. The decrease in insulin-stimulated glucose uptake due to ZFP407 deficiency was attributed to a reduction in GLUT4 mRNA and protein levels. The decrease in GLUT4 was due to both decreased transcription of Glut4 mRNA and decreased efficiency of Glut4 pre-mRNA splicing. Interestingly, ZFP407 coordinately regulated this decrease in transcription with an increase in the stability of Glut4 mRNA, resulting in opposing effects on steady-state Glut4 mRNA levels. More broadly, transcriptome analysis revealed that ZFP407 regulates many peroxisome proliferator-activated receptor (PPAR) γ target genes beyond Glut4. ZFP407 was required for the PPARγ agonist rosiglitazone to increase Glut4 expression, but was not sufficient to increase expression of a PPARγ target gene reporter construct. However, ZFP407 and PPARγ co-overexpression synergistically activated a PPARγ reporter construct beyond the level of PPARγ alone. Thus, ZFP407 may represent a new modulator of the PPARγ signaling pathway.

[1]  A. Saltiel,et al.  A Rab10:RalA G protein cascade regulates insulin-stimulated glucose uptake in adipocytes , 2014, Molecular biology of the cell.

[2]  R. Marín-Juez,et al.  Mechanisms Regulating GLUT4 Transcription in Skeletal Muscle Cells Are Highly Conserved across Vertebrates , 2013, PloS one.

[3]  A. Olson,et al.  Moderate GLUT4 Overexpression Improves Insulin Sensitivity and Fasting Triglyceridemia in High-Fat Diet–Fed Transgenic Mice , 2013, Diabetes.

[4]  D. James,et al.  Endosomal sorting of GLUT4 and Gap1 is conserved between yeast and insulin-sensitive cells , 2013, Journal of Cell Science.

[5]  Benjamin J. Blencowe,et al.  Dynamic Integration of Splicing within Gene Regulatory Pathways , 2013, Cell.

[6]  Ching-Wei Chang,et al.  Coordinated regulation of synthesis and stability of RNA during the acute TNF-induced proinflammatory response , 2013, Proceedings of the National Academy of Sciences.

[7]  Philipp E. Scherer,et al.  Mitochondrial dysfunction in white adipose tissue , 2012, Trends in Endocrinology & Metabolism.

[8]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[9]  W. Huber,et al.  Detecting differential usage of exons from RNA-seq data , 2012, Genome research.

[10]  J. Bogan.  Regulation of glucose transporter translocation in health and diabetes. , 2012, Annual review of biochemistry.

[11]  Alan R. Saltiel,et al.  Regulation of glucose transport by insulin: traffic control of GLUT4 , 2012, Nature Reviews Molecular Cell Biology.

[12]  K. Inoki,et al.  Rab5 Proteins Regulate Activation and Localization of Target of Rapamycin Complex 1* , 2012, The Journal of Biological Chemistry.

[13]  P. Spitali,et al.  Splice Modulating Therapies for Human Disease , 2012, Cell.

[14]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[15]  Adrian R. Krainer,et al.  Peripheral SMN restoration is essential for long-term rescue of a severe SMA mouse model , 2011, Nature.

[16]  Christopher J. Lyon,et al.  A Peroxisome Proliferator-activated Receptor γ (PPARγ)/PPARγ Coactivator 1β Autoregulatory Loop in Adipocyte Mitochondrial Function* , 2011, The Journal of Biological Chemistry.

[17]  A. Klip,et al.  Endocytosis, recycling, and regulated exocytosis of glucose transporter 4. , 2011, Biochemistry.

[18]  A. Saltiel,et al.  A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action , 2011, Molecular biology of the cell.

[19]  A. Albiston,et al.  GLUT4 associated proteins as therapeutic targets for diabetes. , 2011, Recent patents on endocrine, metabolic & immune drug discovery.

[20]  D. Dixon,et al.  The roles of TTP and BRF proteins in regulated mRNA decay , 2011, Wiley interdisciplinary reviews. RNA.

[21]  Cole Trapnell,et al.  Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. , 2010, Nature biotechnology.

[22]  F. Zwartkruis,et al.  Rap1, a mercenary among the Ras-like GTPases. , 2010, Developmental biology.

[23]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[24]  M. Armoni,et al.  Transcriptional regulation of the insulin-responsive glucose transporter GLUT4 gene: from physiology to pathology. , 2008, American journal of physiology. Endocrinology and metabolism.

[25]  Y. Hua,et al.  Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. , 2008, American journal of human genetics.

[26]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[27]  E. Cuppen,et al.  RAP‐1 and the RAL‐1/exocyst pathway coordinate hypodermal cell organization in Caenorhabditis elegans , 2007, The EMBO journal.

[28]  Qian Wang,et al.  Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c. , 2007, Developmental cell.

[29]  M. Armoni,et al.  Transcriptional regulation of the GLUT4 gene: from PPAR-γ and FOXO1 to FFA and inflammation , 2007, Trends in Endocrinology & Metabolism.

[30]  Brenda F Baker,et al.  Enhancement of SMN2 Exon 7 Inclusion by Antisense Oligonucleotides Targeting the Exon , 2007, PLoS biology.

[31]  I. Verma,et al.  Lentiviral short hairpin ribonucleic acid-mediated knockdown of GLUT4 in 3T3-L1 adipocytes. , 2006, Endocrinology.

[32]  C. Will,et al.  U2 snRNA-Protein Contacts in Purified Human 17S U2 snRNPs and in Spliceosomal A and B Complexes , 2006, Molecular and Cellular Biology.

[33]  A. Saltiel,et al.  TC10 and insulin-stimulated glucose transport. , 2006, Methods in enzymology.

[34]  J. Gustafsson,et al.  Expression of the Insulin-responsive Glucose Transporter GLUT4 in Adipocytes Is Dependent on Liver X Receptor α* , 2003, Journal of Biological Chemistry.

[35]  J. B. Knight,et al.  Regulation of the human GLUT4 gene promoter: Interaction between a transcriptional activator and myocyte enhancer factor 2A , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Hui Chen,et al.  Peroxisome Proliferator-activated Receptor-γ Represses GLUT4 Promoter Activity in Primary Adipocytes, and Rosiglitazone Alleviates This Effect* , 2003, Journal of Biological Chemistry.

[37]  Alan R. Saltiel,et al.  The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin , 2003, Nature.

[38]  Yang Li,et al.  T0070907, a Selective Ligand for Peroxisome Proliferator-activated Receptor γ, Functions as an Antagonist of Biochemical and Cellular Activities* , 2002, The Journal of Biological Chemistry.

[39]  M. Mann,et al.  AU Binding Proteins Recruit the Exosome to Degrade ARE-Containing mRNAs , 2001, Cell.

[40]  J. Olefsky,et al.  Insulin can regulate GLUT4 internalization by signaling to Rab5 and the motor protein dynein , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  H. Lodish,et al.  Insulin-Responsive Compartments Containing GLUT4 in 3T3-L1 and CHO Cells: Regulation by Amino Acid Concentrations , 2001, Molecular and Cellular Biology.

[42]  G. Shulman,et al.  Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver , 2001, Nature.

[43]  J. Torchia,et al.  A Novel Nuclear Receptor Corepressor Complex, N-CoR, Contains Components of the Mammalian SWI/SNF Complex and the Corepressor KAP-1* , 2000, The Journal of Biological Chemistry.

[44]  M. Lane,et al.  Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover. , 1993, Proceedings of the National Academy of Sciences of the United States of America.