PPAR-γ activation restores pancreatic islet SERCA2 levels and prevents β-cell dysfunction under conditions of hyperglycemic and cytokine stress

Tatsuyoshi Kono, Geonyoung Ahn, Dan R. Moss, Liann Gann, Angel Zarain-Herzberg, Yurika Nishiki, Patrick T. Fueger, Takeshi Ogihara, Carmella Evans-Molina

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

The maintenance of intracellular Ca 2+ homeostasis in the pancreatic β-cell is closely regulated by activity of the sarco-endoplasmic reticulum Ca 2+ ATPase (SERCA) pump. Our data demonstrate a loss of β-cell SERCA2b expression in several models of type 2 diabetes including islets from db/db mice and cadaveric diabetic human islets. Treatment of 832/13 rat INS-1-derived cells with 25 mm{cyrillic} glucose and the proinflammatory cytokine IL-1 β led to a similar loss of SERCA2b expression, which was prevented by treatment with the peroxisome proliferator-activated receptor (PPAR)-γ agonist, pioglitazone. Pioglitazone was able to also protect against hyperglycemia and cytokineinduced elevations in cytosolic Ca 2+ levels, insulin-secretory defects, and cell death. To determine whether PPAR-γ was a direct transcriptional regulator of the SERCA2 gene, luciferase assays were performed and showed that a-259 bp region is sufficient to confer PPAR-γ transactivation; EMSA and chromatin immunoprecipitation experiments confirmed that PPAR-γ directly binds a PPAR response element in this proximal region. We next sought to characterize the mechanisms by which SERCA2b was down-regulated. INS-1 cells were exposed to high glucose and IL-1β in time course experiments. Within 2 h of exposure, activation of cyclin-dependent kinase 5 (CDK5) was observed and correlated with increased serine-273 phosphorylation of PPAR-γ and loss of SERCA2 protein expression, findings that were prevented by pioglitazone and roscovitine, a pharmacological inhibitor of CDK5. We conclude that pioglitazone modulates SERCA2b expression through direct transcriptional regulation of the gene and indirectly through prevention of CDK5-induced phosphorylation of PPAR-γ.

Original languageEnglish (US)
Pages (from-to)257-271
Number of pages15
JournalMolecular Endocrinology
Volume26
Issue number2
DOIs
StatePublished - 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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