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Sterol regulatory element–binding protein‐1c and pancreatic β‐cell dysfunction

It has long been known that excess intracellular fatty acids cause impaired insulin secretion, referred to as β‐cell lipotoxicity. Sterol regulatory element–binding protein (SREBP)‐1c is a transcription factor that controls hepatic fatty acid synthesis. Activation of SREBP‐1c by overnutrition also inhibits insulin receptor substrate‐2 (IRS‐2) and induces insulin resistance in the liver. As SREBP‐1c is also expressed in β cells, we hypothesized that activation of SREBP‐1c could be a part of the mechanism by which saturated fatty acids induce β‐cell lipotoxicity. We found that nuclear SREBP‐1c has a negative impact on both glucose‐ and potassium‐stimulated insulin secretion as determined in islets from β‐cell‐specific SREBP‐1c transgenic mice as well as SREBP‐1c knockout mice. This effect of SREBP‐1c involves multiple functional pathways required for insulin secretion from β cells: (i) decreased ATP caused by energy consumption through lipogenesis and uncoupling protein‐2 (UCP‐2) activation; (ii) repressed IRS‐2 and pancreas duodenum homeobox 1 (PDX1) expression, leading to impaired β‐cell mass; and (iii) impaired post‐ATP membrane voltage–dependent steps of the insulin secretion pathway caused by upregulated granuphilin and other ion channel proteins. Saturated fatty acids, such as palmitic acid (PA), impair insulin secretion through SREBP‐1c activation, whereas polyunsaturated fatty acids including eicosapentaenoic acid (EPA) restore PA‐suppressed insulin secretion through suppression of SREBP‐1c. These data implicate a therapeutic potential of EPA against insulin secretion defects caused by lipotoxicity.