Cholesterol Accumulation Increases Insulin Granule Size and Impairs Membrane Trafficking Academic Article uri icon

Overview

MeSH Major

  • Cholesterol
  • Insulin
  • Secretory Vesicles

abstract

  • The formation of mature secretory granules is essential for proper storage and regulated release of hormones and neuropeptides. In pancreatic β cells, cholesterol accumulation causes defects in insulin secretion and may participate in the pathogenesis of type 2 diabetes. Using a novel cholesterol analog, we show for the first time that insulin granules are the major sites of intracellular cholesterol accumulation in live β cells. This is distinct from other, non-secretory cell types, in which cholesterol is concentrated in the recycling endosomes and the trans-Golgi network. Excess cholesterol was delivered specifically to insulin granules, which caused granule enlargement and retention of syntaxin 6 and VAMP4 in granule membranes, with concurrent depletion of these proteins from the trans-Golgi network. Clathrin also accumulated in the granules of cholesterol-overloaded cells, consistent with a possible defect in the last stage of granule maturation, during which clathrin-coated vesicles bud from the immature granules. Excess cholesterol also reduced the docking and fusion of insulin granules at the plasma membrane. Together, the data support a model in which cholesterol accumulation in insulin secretory granules impairs the ability of these vesicles to respond to stimuli, and thus reduces insulin secretion.

publication date

  • November 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3465494

Digital Object Identifier (DOI)

  • 10.1111/j.1600-0854.2012.01407.x

PubMed ID

  • 22889194

Additional Document Info

start page

  • 1466

end page

  • 80

volume

  • 13

number

  • 11