Stimulation of Lipogenesis as Well as Fatty Acid Oxidation Protects against Palmitate-Induced INS-1 β-Cell Death

• Published in: Endocrinology (Philadelphia) 2011-03, Vol.152 (3), p.816-827
• Main Authors: Choi, Sung-E, Jung, Ik-Rak, Lee, Youn-Jung, Lee, Soo-Jin, Lee, Ji-Hyun, Kim, Youngsoo, Jun, Hee-Sook, Lee, Kwan-Woo, Park, Chan Bae, Kang, Yup
• Format: Article
• Language: English
• Subjects: Acyltransferase; Agonists; Animals; Beta cells; Bezafibrate; Biological and medical sciences; c-Jun protein; Carnitine; CCAAT/enhancer-binding protein; Cell activation; Cell death; Cells, Cultured; Cellular stress response; Cytotoxicity; Down-regulation; Endoplasmic Reticulum; Fatty acids; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Glycerol; Glycerol-3-phosphate; Hepatocytes; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Intermediates; Kinases; Lipid Metabolism; Lipids; Lipogenesis; Lipogenesis - drug effects; Liver X Receptors; Metabolism; Mortality; Orphan Nuclear Receptors - agonists; Oxidation; Oxidation-Reduction; Palmitates - pharmacology; Palmitic acid; Peroxisome proliferator-activated receptors; Proteins; Rats; Receptors; Sterol regulatory element-binding protein; Stimulation; Toxicity; Transcription factors; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0924

Stimulation of lipid metabolism, including synthesis and oxidation, protects palmitate-induced cytotoxicity to β-cells. Saturated fatty acids are generally cytotoxic to β-cells. Accumulation of lipid intermediates and subsequent activation of lipid-mediated signals has been suggested to play a role in fatty acid-induced toxicity. To determine the effects of lipid metabolism in fatty acid-induced toxicity, lipid metabolism was modulated by up- and down-regulation of a lipogenic or fatty acid oxidation pathway, and the effects of various modulators on palmitate (PA)-induced INS-1 β-cell death were then evaluated. Treatment with the liver X receptor agonist T0901317 reduced PA-induced INS-1 cell death, regardless of its enhanced lipogenic activity. Furthermore, transient expression of a lipogenic transcription factor sterol regulatory element binding protein-1c (SREBP-1c) was also protective against PA-induced cytotoxicity. In contrast, knockdown of SREBP-1c or glycerol-3-phosphate acyltransferase 1 significantly augmented PA-induced cell death and reduced T0901317-induced protective effects. Conversely, T0901317 increased carnitine PA transferease-1 (CPT-1) expression and augmented PA oxidation. CPT-1 inhibitor etomoxir or CPT-1 knockdown augmented PA-induced cell death and reduced T0901317-induced protective effects, whereas the peroxisome proliferator-activated receptor (PPAR)-α agonist bezafibrate reduced PA-induced toxicity. In particular, T0901317 reduced the levels of PA-induced endoplasmic reticulum (ER) stress markers, including phospho-eukaryotic initiation factor-2α, phospho-C-Jun N terminal kinase, and CCAAT/enhancer-binding protein homologous protein. In contrast, knockdown of SREBP-1c or glycerol-3-phosphate acyltransferase 1 augmented PA-induced ER stress responses. Results of these experiments suggested that stimulation of lipid metabolism, including lipogenesis and fatty acid oxidation, protected β-cells from PA-induced lipotoxicity and that protection through enhanced lipogenesis was likely due to reduced ER stress.