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Department of Geriatrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Department of Geriatrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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analysis revealed that circ-Tulp4 was regulated by NEFA in Min6 cells, suggesting that the low expression of circ-Tulp4 might be related to β-cell lipotoxicity and the development of T2DM. Circ-Tulp4 maintained β-cell function under lipotoxic
Department of Medical Biochemistry and Genetics, University of Copenhagen, 2200 Copenhagen N, Denmark.
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Department of Medical Biochemistry and Genetics, University of Copenhagen, 2200 Copenhagen N, Denmark.
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Department of Medical Biochemistry and Genetics, University of Copenhagen, 2200 Copenhagen N, Denmark.
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Department of Medical Biochemistry and Genetics, University of Copenhagen, 2200 Copenhagen N, Denmark.
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Tight regulation of fatty acid metabolism in pancreatic β-cells is important for β-cell viability and function. Chronic exposure to elevated concentrations of fatty acid is associated with β-cell lipotoxicity. Glucose is known to repress fatty acid oxidation and hence to augment the toxicity of fatty acids. The peroxisome proliferator activated receptor α (PPARα) is a key activator of genes involved in β-cell fatty acid oxidation, and transcription of the PPARα gene has been shown to be repressed by increasing concentrations of glucose in β-cells. However, the mechanism underlying this transcriptional repression by glucose remains unclear. Here we report that glucose-induced repression of PPARα gene expression in INS-1E cells is independent of β-cell excitation and insulin secretion but requires activation of protein phosphatase 2A in a process involving inactivation of the AMP-activated protein kinase (AMPK). Pharmacological activation of AMPK at high glucose concentrations interferes with glucose repression of PPARα and PPARα target genes in INS-1E cells as well as in rat islets. Specific knock-down of the catalytic AMPK-subunit AMPKα2 but not AMPKα1 using RNAi suppressed PPARα expression, thereby mimicking the effect of glucose. These results indicate that activation of protein phosphatase 2A and subsequent inactivation of AMPK is necessary for glucose repression of PPARα expression in pancreatic β-cells.
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Molecular Neuroscience Group, Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia
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Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
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– 5541 . ( https://doi.org/10.1210/jc.2004-0150 ) 10.1210/jc.2004-0150 Marmugi A Parnis J Chen X Carmichael L Hardy J Mannan N Marchetti P Piemonti L Bosco D Johnson P , 2016 Sorcin links pancreatic β-Cell lipotoxicity to ER Ca2+ stores . Diabetes
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β-cell dysfunction ( Brunham et al. 2008 , Kruit et al. 2010 ). In pancreatic β-cells, lipotoxicity induced by cholesterol accumulation results in apoptosis and impaired insulin secretion ( Unger 1995 , Zhou & Grill 1995 ). ATP-binding cassette
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Kadowaki T 2004 Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a β-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c . Endocrinology 145
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β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-β-cell relationships. PNAS 91 10878 –10882. Listenberger LL , Ory DS & Schaffer JE 2001
