PMID- 20530872
OWN - NLM
STAT- MEDLINE
DCOM- 20100727
LR  - 20211020
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 120
IP  - 7
DP  - 2010 Jul
TI  - An intracellular role for ABCG1-mediated cholesterol transport in the regulated 
      secretory pathway of mouse pancreatic beta cells.
PG  - 2575-89
LID - 41280 [pii]
LID - 10.1172/JCI41280 [doi]
AB  - Cholesterol is a critical component of cell membranes, and cellular cholesterol 
      levels and distribution are tightly regulated in mammals. Recent evidence has 
      revealed a critical role for pancreatic beta cell-specific cholesterol 
      homeostasis in insulin secretion as well as in beta cell dysfunction in diabetes 
      and the metabolic response to thiazolidinediones (TZDs), which are antidiabetic 
      drugs. The ATP-binding cassette transporter G1 (ABCG1) has been shown to play a 
      role in cholesterol efflux, but its role in beta cells is currently unknown. In 
      other cell types, ABCG1 expression is downregulated in diabetes and upregulated 
      by TZDs. Here we have demonstrated an intracellular role for ABCG1 in beta cells. 
      Loss of ABCG1 expression impaired insulin secretion both in vivo and in vitro, 
      but it had no effect on cellular cholesterol content or efflux. Subcellular 
      localization studies showed the bulk of ABCG1 protein to be present in insulin 
      granules. Loss of ABCG1 led to altered granule morphology and reduced granule 
      cholesterol levels. Administration of exogenous cholesterol restored granule 
      morphology and cholesterol content and rescued insulin secretion in 
      ABCG1-deficient islets. These findings suggest that ABCG1 acts primarily to 
      regulate subcellular cholesterol distribution in mouse beta cells. Furthermore, 
      islet ABCG1 expression was reduced in diabetic mice and restored by TZDs, 
      implicating a role for regulation of islet ABCG1 expression in diabetes 
      pathogenesis and treatment.
FAU - Sturek, Jeffrey M
AU  - Sturek JM
AD  - Department of Pharmacology, University of Virginia School of Medicine, 
      Charlottesville, Virginia, USA.
FAU - Castle, J David
AU  - Castle JD
FAU - Trace, Anthony P
AU  - Trace AP
FAU - Page, Laura C
AU  - Page LC
FAU - Castle, Anna M
AU  - Castle AM
FAU - Evans-Molina, Carmella
AU  - Evans-Molina C
FAU - Parks, John S
AU  - Parks JS
FAU - Mirmira, Raghavendra G
AU  - Mirmira RG
FAU - Hedrick, Catherine C
AU  - Hedrick CC
LA  - eng
GR  - K08 DK080225/DK/NIDDK NIH HHS/United States
GR  - R01 HL094525/HL/NHLBI NIH HHS/United States
GR  - K08 DK 80225/DK/NIDDK NIH HHS/United States
GR  - R01 DK060581/DK/NIDDK NIH HHS/United States
GR  - R01 HL097368/HL/NHLBI NIH HHS/United States
GR  - R01 DK073380/DK/NIDDK NIH HHS/United States
GR  - P01 HL055798/HL/NHLBI NIH HHS/United States
GR  - P01 HL049373/HL/NHLBI NIH HHS/United States
GR  - P01 HL55798/HL/NHLBI NIH HHS/United States
GR  - R01 DK60581/DK/NIDDK NIH HHS/United States
GR  - R01 HL085790/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100607
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - ATP-Binding Cassette Transporters/biosynthesis/*genetics/*metabolism
MH  - Animals
MH  - Biological Transport/genetics
MH  - Cell Membrane/genetics/metabolism
MH  - Cholesterol/genetics/*metabolism
MH  - Cytoplasm/genetics/metabolism
MH  - Diabetes Mellitus, Type 2/genetics/metabolism
MH  - Down-Regulation
MH  - Insulin-Secreting Cells/metabolism
MH  - Lipid Metabolism/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Mutant Strains
MH  - Secretory Pathway
PMC - PMC2898593
EDAT- 2010/06/10 06:00
MHDA- 2010/07/28 06:00
PMCR- 2010/06/07
CRDT- 2010/06/10 06:00
PHST- 2009/09/29 00:00 [received]
PHST- 2010/04/14 00:00 [accepted]
PHST- 2010/06/10 06:00 [entrez]
PHST- 2010/06/10 06:00 [pubmed]
PHST- 2010/07/28 06:00 [medline]
PHST- 2010/06/07 00:00 [pmc-release]
AID - 41280 [pii]
AID - 10.1172/JCI41280 [doi]
PST - ppublish
SO  - J Clin Invest. 2010 Jul;120(7):2575-89. doi: 10.1172/JCI41280. Epub 2010 Jun 7.