title: Zinc finger protein 407 (ZFP407) regulates insulin-stimulated glucose uptake and glucose transporter 4 (Glut4) mRNA.
abstract: 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.
authors.affiliation: From the Departments of Genetics and Genome Sciences and Biological Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, dab22@case.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Buchner
authors.affiliation: From the Departments of Genetics and Genome Sciences and.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Charrier
authors.affiliation: the Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Ethan
authors.initials: E
authors.lastname: Srinivasan
authors.affiliation: From the Departments of Genetics and Genome Sciences and.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: the Department of Oncology, Division of Radiation and Cancer Biology, University of Michigan Cancer Center, Ann Arbor, Michigan 48109.
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Paulsen
authors.affiliation: the Department of Oncology, Division of Radiation and Cancer Biology, University of Michigan Cancer Center, Ann Arbor, Michigan 48109.
authors.forename: Mats
authors.initials: M
authors.lastname: Ljungman
authors.affiliation: the Department of Physiology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163, and the Children's Foundation Research Institute, Le Bonheur Children's Hospital, Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, Tennessee 38103.
authors.forename: Dave
authors.initials: D
authors.lastname: Bridges
authors.affiliation: the Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, saltiel@lsi.umich.edu.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D047495:PPAR gamma; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; C580839:ZNF407 protein, human; D005947:Glucose
keywords: Adipocyte; Glucose Transport; Glucose Transporter Type 4 (GLUT4); Insulin; Peroxisome Proliferator-activated Receptor (PPAR); Transcription Regulation; Type 2 Diabetes; Zinc Finger; mRNA Decay