title: 4-Phenylbutyric acid increases GLUT4 gene expression through suppression of HDAC5 but not endoplasmic reticulum stress.
abstract: BACKGROUND
  The chemical chaperone 4-phenylbutyric acid (4-PBA) has been shown to relieve endoplasmic reticulum (ER) stress. Therefore, it improves insulin sensitivity and promotes glucose metabolism in skeletal muscle. Glucose transporter type 4 (GLUT4), as a major glucose transporter protein, plays a central role in glucose metabolism. Until now, it has been unclear whether 4-PBA affects GLUT4 gene expression and thus, contributes to glucose metabolism.
  
  
  METHODS
  C2C12 myotubes were treated with 4-PBA, tunicamycin or butyrate and subjected to Western blot and RT-PCR.
  
  
  RESULTS
  4-PBA-treated C2C12 myotubes increased GLUT4 expression and promoted glucose metabolism. Most interestingly, GLUT4 gene expression induced by 4-PBA was not associated with ER stress even in the presence of tunicamycin, an ER stress inducer. Moreover, we also found that 4-PBA inhibited histonedeacetylase 5 (HDAC5) expression in C2C12 myotubes, resulting in hyperacetylation of the histone H3 at the myocyte enhancer factor 2 (MEF2) binding site. This increased the binding of MEF2A to the site on the GLUT4 promoter, resulting in increased GLUT4 expression.
  
  
  CONCLUSIONS
  Our data indicate that 4-PBA increases GLUT4 expression by acetylating the MEF2 site to increase the MEF2A binding through a mechanism that involves suppression of the HDAC5 pathway, but without involving ER stress.
authors.forename: Hailong
authors.initials: H
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Changlin
authors.initials: C
authors.lastname: Wang
authors.forename: Hongjuan
authors.initials: H
authors.lastname: He
authors.forename: Ke
authors.initials: K
authors.lastname: Mao
authors.forename: Xiao
authors.initials: X
authors.lastname: Ma
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Shi
authors.forename: Yuri
authors.initials: Y
authors.lastname: Oh
authors.forename: FengWei
authors.initials: F
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D002087:Butyrates; D051275:Glucose Transporter Type 4; D006657:Histones; D064326:MEF2 Transcription Factors; D010654:Phenylbutyrates; C495693:Slc2a4 protein, mouse; D014415:Tunicamycin; C075773:4-phenylbutyric acid; D006003:Glycogen; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D005947:Glucose