title: Stimulation of lipogenesis as well as fatty acid oxidation protects against palmitate-induced INS-1 beta-cell death.
abstract: 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.
authors.affiliation: Institute for Medical Science, Ajou University School of Medicine, Wonchon-dong san 5, Yeongtong-gu, Suwon, Gyeonggi-do 442-749, Republic of Korea.
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.forename: Ik-Rak
authors.initials: IR
authors.lastname: Jung
authors.forename: Youn-Jung
authors.initials: YJ
authors.lastname: Lee
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
authors.forename: Kwan-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Chan Bae
authors.initials: CB
authors.lastname: Park
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum; D005227:Fatty Acids / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology*; D050356:Lipid Metabolism; D050155:Lipogenesis / Q000187:drug effects*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists; D010084:Oxidation-Reduction; D010168:Palmitates / Q000494:pharmacology*; D051381:Rats
chemical_list: D005227:Fatty Acids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010168:Palmitates