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A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Sterol regulatory element-binding protein-1c and pancreatic beta-cell dysfunction
H Shimano1, M Amemiya-Kudo, A Takahashi
1Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. hshimano@md.tsukuba.ac.jp
Diabetes, Obesity & Metabolism
|October 9, 2007
Summary
Sterol regulatory element-binding protein (SREBP)-1c activation by saturated fatty acids impairs insulin secretion from beta cells. Polyunsaturated fatty acids like eicosapentaenoic acid (EPA) may restore insulin secretion by suppressing SREBP-1c.
Area of Science:
- Metabolism
- Endocrinology
- Molecular Biology
Background:
- Excess intracellular fatty acids cause beta-cell lipotoxicity, impairing insulin secretion.
- Sterol regulatory element-binding protein (SREBP)-1c regulates fatty acid synthesis and insulin resistance in the liver.
- SREBP-1c is also expressed in pancreatic beta cells, suggesting a role in lipotoxicity.
Purpose of the Study:
- To investigate the role of SREBP-1c activation in saturated fatty acid-induced beta-cell lipotoxicity.
- To elucidate the molecular mechanisms by which SREBP-1c affects insulin secretion.
- To explore the potential of fatty acids in modulating SREBP-1c activity and insulin secretion.
Main Methods:
- Utilized beta-cell-specific SREBP-1c transgenic and knockout mouse models.
- Assessed glucose- and potassium-stimulated insulin secretion from isolated islets.
- Analyzed key molecular pathways including ATP production, gene expression (IRS-2, PDX1), and ion channel protein levels.
Main Results:
- Nuclear SREBP-1c negatively impacts glucose- and potassium-stimulated insulin secretion.
- SREBP-1c activation leads to decreased ATP, repressed IRS-2 and PDX1 expression, and impaired beta-cell mass.
- Saturated fatty acids (e.g., palmitic acid) activate SREBP-1c, while polyunsaturated fatty acids (e.g., eicosapentaenoic acid) suppress it, restoring insulin secretion.
Conclusions:
- SREBP-1c activation is a key mechanism in saturated fatty acid-induced beta-cell lipotoxicity.
- Therapeutic strategies targeting SREBP-1c, such as using eicosapentaenoic acid, show potential for treating insulin secretion defects.
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