Sterol regulatory element-binding protein-1c and pancreatic beta-cell dysfunction.
It has long been known that excess intracellular fatty acids cause impaired insulin secretion, referred to as beta-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 beta cells, we hypothesized that activation of SREBP-1c could be a part of the mechanism by which saturated fatty acids induce beta-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 beta-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 beta 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 beta-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.
Shimano
H
H
Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. hshimano@md.tsukuba.ac.jp
Amemiya-Kudo
M
M
Takahashi
A
A
Kato
T
T
Ishikawa
M
M
Yamada
N
N
D000818:Animals; D005227:Fatty Acids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
D005227:Fatty Acids; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D051780:Sterol Regulatory Element Binding Protein 1; D005947:Glucose