Pancreatic beta-cell lipotoxicity induced by overexpression of hormone-sensitive lipase.
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.
Winzell
Maria Sörhede
MS
Department of Cell and Molecular Biology, Lund University, Lund, Sweden. maria.sorhede_winzell@medkem.lu.se
Svensson
Håkan
H
Enerbäck
Sven
S
Ravnskjaer
Kim
K
Mandrup
Susanne
S
Esser
Victoria
V
Arner
Peter
P
Alves-Guerra
Marie-Clotilde
MC
Miroux
Bruno
B
Sundler
Frank
F
Ahrén
Bo
B
Holm
Cecilia
C
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
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