Open AccessExendin‐4 regulates pancreatic ABCA1 transcription via CaMKK/CaMKIV pathway
Author(s) -
Li Junhua,
Murao Koji,
Imachi Hitomi,
Masugata Hisashi,
Iwama Hisakazu,
Tada Satoshi,
Zhang GuoXing,
Kobayashi Ryoji,
Ishida Toshihiko,
Tokumitsu Hiroshi
Publication year - 2010
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00955.x
Subject(s) - abca1 , biology , protein kinase a , gene knockdown , phosphorylation , medicine , endocrinology , phosphoenolpyruvate carboxykinase , kinase , microbiology and biotechnology , gene , biochemistry , transporter
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 Ca 2+ /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 (Thr 196 ) 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 Thr 196 ) 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.