Exendin-4 regulates pancreatic ABCA1 transcription via CaMKK/CaMKIV pathway

Junhua Li, Koji Murao, Hitomi Imachi, Hisashi Masugata, Hisakazu Iwama, Satoshi Tada, Guo Xing Zhang, Ryoji Kobayashi, Toshihiko Ishida, Hiroshi Tokumitsu

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

ATP-binding cassette transporter A1 (ABCA1) in pancreatic β cells influences insulin secretion and glucose homeostasis. This study investigates whether the long-acting agonist of the glucagon-like peptide 1, namely exendin-4, which mediates stimulatory effects on ABCA1 gene expression, could interfere with the Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) cascade. ABCA1 promoter activity was examined by reporter gene assay in rat insulin-secreting INS-1 cells incubated with exendin-4. CaMKIV activity was assessed by detection of activation-loop phosphorylation (Thr196) of CaMKIV. We investigated the influence of the constitutively active form (CaMKIVc) or CaMKIV knockdown on ABCA1 expression. Increased abundance of ABCA1 protein was noted in response to rising concentrations of exendin-4 with maximum induction at 10 nM. Exendin-4 also stimulated ABCA1 promoter activity, but failed to do so in the presence of STO-609, a CaMKK inhibitor. Up-regulation of CaMKIV phosphorylation (at Thr196) peaked after 10 min. of exposure to exendin-4. CaMKIVc enhanced or up-regulated ABCA1 promoter activity in INS-1 cells. Furthermore, exendin-4 induction of ABCA1 protein expression was significantly suppressed in cells treated with CaMKIV-siRNA. Activation of the CaMKK/CaMKIV cascade by exendin-4 stimulated ABCA1 gene transcription, indicating that exendin-4 plays an important role in insulin secretion and cholesterol ester content in pancreatic β cells.

Original languageEnglish
Pages (from-to)1083-1087
Number of pages5
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number5
DOIs
Publication statusPublished - Jul 23 2010
Externally publishedYes

Keywords

  • ABCA1
  • CaMKK/CaMKIV
  • Exendin-4
  • GLP-1
  • Transcription

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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  • Cite this

    Li, J., Murao, K., Imachi, H., Masugata, H., Iwama, H., Tada, S., Zhang, G. X., Kobayashi, R., Ishida, T., & Tokumitsu, H. (2010). Exendin-4 regulates pancreatic ABCA1 transcription via CaMKK/CaMKIV pathway. Journal of Cellular and Molecular Medicine, 14(5), 1083-1087. https://doi.org/10.1111/j.1582-4934.2009.00955.x