title: ChREBP mediates glucose-stimulated pancreatic β-cell proliferation.
abstract: Glucose stimulates rodent and human β-cell replication, but the intracellular signaling mechanisms are poorly understood. Carbohydrate response element-binding protein (ChREBP) is a lipogenic glucose-sensing transcription factor with unknown functions in pancreatic β-cells. We tested the hypothesis that ChREBP is required for glucose-stimulated β-cell proliferation. The relative expression of ChREBP was determined in liver and β-cells using quantitative RT-PCR (qRT-PCR), immunoblotting, and immunohistochemistry. Loss- and gain-of-function studies were performed using small interfering RNA and genetic deletion of ChREBP and adenoviral overexpression of ChREBP in rodent and human β-cells. Proliferation was measured by 5-bromo-2'-deoxyuridine incorporation, [(3)H]thymidine incorporation, and fluorescence-activated cell sorter analysis. In addition, the expression of cell cycle regulatory genes was measured by qRT-PCR and immunoblotting. ChREBP expression was comparable with liver in mouse pancreata and in rat and human islets. Depletion of ChREBP decreased glucose-stimulated proliferation in β-cells isolated from ChREBP(-/-) mice, in INS-1-derived 832/13 cells, and in primary rat and human β-cells. Furthermore, depletion of ChREBP decreased the glucose-stimulated expression of cell cycle accelerators. Overexpression of ChREBP amplified glucose-stimulated proliferation in rat and human β-cells, with concomitant increases in cyclin gene expression. In conclusion, ChREBP mediates glucose-stimulated proliferation in pancreatic β-cells.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Metukuri
authors.forename: Pili
authors.initials: P
authors.lastname: Zhang
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Basantani
authors.forename: Connie
authors.initials: C
authors.lastname: Chin
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Stamateris
authors.forename: Laura C
authors.initials: LC
authors.lastname: Alonso
authors.forename: Karen K
authors.initials: KK
authors.lastname: Takane
authors.forename: Roberto
authors.initials: R
authors.lastname: Gramignoli
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
authors.forename: Robert M
authors.initials: RM
authors.lastname: O'Doherty
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Stewart
authors.forename: Rupangi C
authors.initials: RC
authors.lastname: Vasavada
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocaña
authors.forename: Donald K
authors.initials: DK
authors.lastname: Scott
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007340:Insulinoma / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D051381:Rats; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; C442825:Mlxipl protein, rat; D009687:Nuclear Proteins; D014157:Transcription Factors; D005947:Glucose