title: Pancreatic beta-cell lipotoxicity induced by overexpression of hormone-sensitive lipase.
abstract: Lipid perturbations associated with triglyceride overstorage in beta-cells impair insulin secretion, a process termed lipotoxicity. To assess the role of hormone-sensitive lipase, which is expressed and enzymatically active in beta-cells, in the development of lipotoxicity, we generated transgenic mice overexpressing hormone-sensitive lipase specifically in beta-cells. Transgenic mice developed glucose intolerance and severely blunted glucose-stimulated insulin secretion when challenged with a high-fat diet. As expected, both lipase activity and forskolin-stimulated lipolysis was increased in transgenic compared with wild-type islets. This was reflected in significantly lower triglycerides levels in transgenic compared with wild-type islets in mice receiving the high-fat diet, whereas no difference in islet triglycerides was found between the two genotypes under low-fat diet conditions. Our results highlight the importance of mobilization of the islet triglyceride pool in the development of beta-cell lipotoxicity. We propose that hormone-sensitive lipase is involved in mediating beta-cell lipotoxicity by providing ligands for peroxisome proliferator-activated receptors and other lipid-activated transcription factors, which in turn alter the expression of critical genes. One such gene might be uncoupling protein-2, which was found to be upregulated in transgenic islets, a change that was accompanied by decreased ATP levels.
authors.affiliation: Department of Cell and Molecular Biology, Lund University, Lund, Sweden. maria.sorhede_winzell@medkem.lu.se
authors.forename: Maria Sörhede
authors.initials: MS
authors.lastname: Winzell
authors.forename: Håkan
authors.initials: H
authors.lastname: Svensson
authors.forename: Sven
authors.initials: S
authors.lastname: Enerbäck
authors.forename: Kim
authors.initials: K
authors.lastname: Ravnskjaer
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
authors.forename: Victoria
authors.initials: V
authors.lastname: Esser
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.forename: Marie-Clotilde
authors.initials: MC
authors.lastname: Alves-Guerra
authors.forename: Bruno
authors.initials: B
authors.lastname: Miroux
authors.forename: Frank
authors.initials: F
authors.lastname: Sundler
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.forename: Cecilia
authors.initials: C
authors.lastname: Holm
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D051273:Glucose Transporter Type 2; D007150:Immunohistochemistry; D007473:Ion Channels; D007515:Islets of Langerhans / Q000737:chemistry / Q000201:enzymology* / Q000254:growth & development; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D010084:Oxidation-Reduction; D010641:Phenotype; D011506:Proteins / Q000378:metabolism; D051381:Rats; D002787:Sterol Esterase / Q000235:genetics* / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D051273:Glucose Transporter Type 2; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins; D011506:Proteins; D014280:Triglycerides; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D002787:Sterol Esterase