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Sterol regulatory element‐binding protein‐1c knockdown protected INS‐1E cells from lipotoxicity
Author(s) -
Li J.,
Liu X.,
Ran X.,
Chen J.,
Li X.,
Wu W.,
Huang H.,
Huang H.,
Long Y.,
Liang J.,
Cheng J.,
Tian H.
Publication year - 2010
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2009.01093.x
Subject(s) - medicine , endocrinology , lipotoxicity , sterol regulatory element binding protein , ampk , beta cell , biology , gene knockdown , chemistry , insulin , apoptosis , microbiology and biotechnology , protein kinase a , insulin resistance , kinase , biochemistry , islet , sterol , cholesterol
Objective: The reduction in insulin secretory capacity and β‐cell mass has been attributed, at least partially, to lipotoxicity, which may contribute to the development of type 2 diabetes. Chronic free fatty acids (FFA) exposure impairs pancreatic β‐cell function and induces β‐cell apoptosis. This study is to elucidate the underlying molecular mechanisms. Research design and methods: We exposed INS‐1E pancreatic β‐cell line to palmitate or oleate, and measured the glucose stimulated insulin secretion (GSIS). The effect of FFA on sterol regulatory element‐binding protein (SREBP)‐1c lipogenic pathway, and expression of genes involved in β‐cell functions, including AMPK (AMP‐activated protein kinase), UCP‐2 (uncoupling protein‐2), IRS‐2 (insulin receptor substrate‐2), PDX‐1 (pancreatic duodenal homeobox‐1), GLUT‐2 (glucose transporter‐2) and B cell lymphoma/leukaemia‐2 (Bcl‐2) were investigated. Apoptosis of these exposed cells was determined by MitoCapture, Annexin V‐Cy3 or terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling assay. Cell lipid accumulation was measured by oil red O staining or TG extraction. Also SREBP‐1c expression knockdown were used. Results: FFA treatment resulted in SREBP‐1c overexpression, impaired GSIS, lipid accumulation, apoptosis of INS‐1E cells. In addition, the expression of lipogenic genes and UCP‐2 were upregulated, but AMPK, IRS‐2, PDX‐1, GLUT‐2 and Bcl‐2 were downregulated in the exposed cells. However, these lipotoxic effects of FFA were largely prevented by induction of a SREBP‐1c small interfering RNA. Conclusions: These data suggest a strong correlation between FFA treatment and SREBP‐1c activation in INS‐1E cells. SREBP‐1c might be a major factor responsible for β‐cell lipotoxicity, and SREBP‐1c knockdown could protect INS‐1E cells from lipotoxicity, which is implicating a therapeutic potential for treating diabetes related to lipotoxicity.