Title | ChREBP mediates glucose-stimulated pancreatic β-cell proliferation. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Metukuri MR, Zhang P, Basantani MK, Chin C, Stamateris RE, Alonso LC, Takane KK, Gramignoli R, Strom SC, O'Doherty RM, Stewart AF, Vasavada RC, Garcia-Ocaña A, Scott DK |
Journal | Diabetes |
Volume | 61 |
Issue | 8 |
Pagination | 2004-15 |
Date Published | 2012 Aug |
ISSN | 1939-327X |
Keywords | Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Cycle Proteins, Cell Proliferation, Glucose, Humans, Insulin-Secreting Cells, Insulinoma, Mice, Nuclear Proteins, Rats, Transcription Factors |
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. |
DOI | 10.2337/db11-0802 |
Alternate Journal | Diabetes |
PubMed ID | 22586588 |
PubMed Central ID | PMC3402328 |
Grant List | DK077096 / DK / NIDDK NIH HHS / United States DKR0155023 / / PHS HHS / United States DK U-01 89538 / DK / NIDDK NIH HHS / United States R01 DK078060 / DK / NIDDK NIH HHS / United States K08 DK076562 / DK / NIDDK NIH HHS / United States DK078060 / DK / NIDDK NIH HHS / United States R56 DK065149 / DK / NIDDK NIH HHS / United States R01 DK077096 / DK / NIDDK NIH HHS / United States R56DK065149 / DK / NIDDK NIH HHS / United States |