Lack of cholesterol mobilization in islets of hormone-sensitive lipase deficient mice impairs insulin secretion.
The observations that hormone-sensitive lipase (HSL) is located in close association to insulin granules in beta-cells and that cholesterol ester hydrolase activity is completely blunted in islets of HSL null mice made us hypothesize that the role of HSL in beta-cells is to provide cholesterol for the exocytosis of insulin. To test this hypothesis, wild type (wt) and HSL null islets were depleted of plasma membrane cholesterol using methyl-beta-cyclodextrin (mbetacd). A significant reduction in insulin secretion from HSL null islets was observed whereas wt islets were unaffected. Using synaptosomal protein of 25 kDa (SNAP-25) as indicator of cholesterol-rich microdomains, confocal microscopy was used to show that HSL null beta-cells treated with mbetacd contained fewer clusters than wt beta-cells. These results indicate that HSL plays an important role in insulin secretion by providing free cholesterol for the formation and maintenance of cholesterol-rich patches for docking of SNARE-proteins to the plasma membrane.
Larsson
Sara
S
Department of Experimental Medical Science, Division of Diabetes, Metabolism and Endocrinology, Lund University, BMC C11, SE-221 84 Lund, Sweden. sara.larsson@med.lu.se
Wierup
Nils
N
Sundler
Frank
F
Eliasson
Lena
L
Holm
Cecilia
C
D000818:Animals; D027201:Cationic Amino Acid Transporter 1 / Q000096:biosynthesis; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D002787:Sterol Esterase / Q000235:genetics / Q000502:physiology*; D050825:Synaptosomal-Associated Protein 25 / Q000032:analysis / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000494:pharmacology
D027201:Cationic Amino Acid Transporter 1; D007328:Insulin; C420826:Slc7a1 protein, mouse; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D002787:Sterol Esterase