title: Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3.
abstract: Fibroblast growth factor 21, a novel regulator of glucose and lipid metabolism, has robust protective properties in neurons. However, its expression and function in glia are unknown. Valproic acid, a mood stabilizer and anticonvulsant, is a histone deacetylase inhibitor and a dynamic gene regulator. We investigated whether histone deacetylase inhibition by valproic acid and other inhibitors upregulates fibroblast growth factor 21 expression and, if so, sought to identify the histone deacetylase isoform(s) involved and their role in altering glial cell morphology.
  
  
  
  C6 glioma or primary cortical glial cultures were treated with histone deacetylase inhibitors, and fibroblast growth factor 21 levels and length of cell processes were subsequently measured. Histone deacetylase 1, 2, or 3 was also knocked down to detect which isoform was involved in regulating fibroblast growth factor 21 mRNA levels. Finally, knockdown and overexpression of fibroblast growth factor 21 were performed to determine whether it played a role in regulating cell process length.
  
  
  
  Treatment of C6 cells or primary glial cultures with valproic acid elevated fibroblast growth factor 21 mRNA levels, extended cell process length, and markedly increased acetylated histone-H3 levels. Other histone deacetylase inhibitors including pan- and class I-specific inhibitors, or selective knockdown of histone deacetylase 2 or 3 isoform produced similar effects. Knockdown or overexpression of fibroblast growth factor 21 significantly decreased or increased C6 cell process length, respectively.
  
  
  
  In glial cell line and primary glia, using pharmacological inhibition and selective gene silencing of histone deacetylases to boost fibroblast growth factor 21 mRNA levels results in elongation of cell processes. Our study provides a new mechanism via which histone deacetylase 2 and 3 participate in upregulating fibroblast growth factor 21 transcription and extending process outgrowth in glia.
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD. chuang@mail.nih.gov lengy@mail.nih.gov.
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Junyu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Liao
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Monica
authors.initials: M
authors.lastname: Wei
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Peter
authors.initials: P
authors.lastname: Leeds
authors.affiliation: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD. chuang@mail.nih.gov lengy@mail.nih.gov.
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects*; D005346:Fibroblast Growth Factors / Q000096:biosynthesis*; D055785:Gene Knockdown Techniques; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D009457:Neuroglia / Q000187:drug effects; D061251:Primary Cell Culture; D015854:Up-Regulation / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*; D000099186:Histone Deacetylase 3
chemical_list: D005346:Fibroblast Growth Factors; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D007527:Isoenzymes; D014635:Valproic Acid; D000099186:Histone Deacetylase 3; C414620:fibroblast growth factor 21
keywords: FGF21; HDAC inhibitors; cell processes; glial cells; valproic acid