title: The role of the Niemann-Pick disease, type C1 protein in adipocyte insulin action.
abstract: The Niemann-Pick disease, type C1 (NPC1) gene encodes a transmembrane protein involved in cholesterol efflux from the lysosome. SNPs within NPC1 have been associated with obesity and type 2 diabetes, and mice heterozygous or null for NPC1 are insulin resistant. However, the molecular mechanism underpinning this association is currently undefined. This study aimed to investigate the effects of inhibiting NPC1 function on insulin action in adipocytes. Both pharmacological and genetic inhibition of NPC1 impaired insulin action. This impairment was evident at the level of insulin signalling and insulin-mediated glucose transport in the short term and decreased GLUT4 expression due to reduced liver X receptor (LXR) transcriptional activity in the long-term. These data show that cholesterol homeostasis through NPC1 plays a crucial role in maintaining insulin action at multiple levels in adipocytes.
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Rachael
authors.initials: R
authors.lastname: Fletcher
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gribben
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Xuiquan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Burchfield
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Kristen C
authors.initials: KC
authors.lastname: Thomas
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: James R
authors.initials: JR
authors.lastname: Krycer
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Fazakerley
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D051379:Mice; D000077296:Niemann-Pick C1 Protein; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000736:Androstenes; D051275:Glucose Transporter Type 4; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D057093:Orphan Nuclear Receptors; D011506:Proteins; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
references.citation: J Clin Invest. 1991 Mar;87(3):1072-81
references.pmid: 1999488
references.citation: Nat Genet. 2009 Feb;41(2):157-9
references.pmid: 19151714
references.citation: Traffic. 2010 Apr;11(4):419-28
references.pmid: 20059748
references.citation: PLoS Genet. 2010 Sep 16;6(9):e1001127
references.pmid: 20862305
references.citation: J Cell Physiol. 2008 Oct;217(1):281-9
references.pmid: 18506777
references.citation: Mol Biol Cell. 2003 Oct;14(10):3967-76
references.pmid: 14517311
references.citation: Biochem Biophys Res Commun. 2012 Aug 3;424(3):482-7
references.pmid: 22776200
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4764-9
references.pmid: 20176935
references.citation: Endocrinology. 2009 Aug;150(8):3493-502
references.pmid: 19406948
references.citation: J Biol Chem. 1997 Nov 28;272(48):30429-38
references.pmid: 9374534
references.citation: FASEB J. 1999 Nov;13(14):1961-71
references.pmid: 10544179
references.citation: J Biol Chem. 1998 Aug 28;273(35):22298-304
references.pmid: 9712847
references.citation: Cell Metab. 2008 May;7(5):421-33
references.pmid: 18460333
references.citation: Mol Cell Biol. 2004 Jul;24(14):6456-66
references.pmid: 15226445
references.citation: Mol Cell. 2008 Oct 10;32(1):140-9
references.pmid: 18851840
references.citation: Nat Genet. 2012 Sep;44(9):981-90
references.pmid: 22885922
references.citation: J Biol Chem. 1996 Oct 25;271(43):26453-6
references.pmid: 8900109
references.citation: Int J Obes (Lond). 2013 Jul;37(7):980-5
references.pmid: 23090577
references.citation: Orphanet J Rare Dis. 2010 Jun 03;5:16
references.pmid: 20525256
references.citation: Nat Genet. 2008 May;40(5):638-45
references.pmid: 18372903
references.citation: Cell. 2009 Jun 26;137(7):1213-24
references.pmid: 19563754
references.citation: J Biol Chem. 2012 Feb 24;287(9):6128-38
references.pmid: 22207758
references.citation: J Cell Biol. 2000 Jun 26;149(7):1455-72
references.pmid: 10871285
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14509-14
references.pmid: 21873248
references.citation: Gene. 2013 Sep 15;527(1):65-70
references.pmid: 23769925
references.citation: EMBO J. 2006 Dec 13;25(24):5648-58
references.pmid: 17139247
references.citation: Mol Biol Cell. 2013 Nov;24(22):3534-44
references.pmid: 24048449
references.citation: J Biol Chem. 1991 Nov 15;266(32):21839-45
references.pmid: 1939208
references.citation: Am J Physiol. 1991 Mar;260(3 Pt 1):C570-80
references.pmid: 2003579
references.citation: J Biol Chem. 1992 Mar 5;267(7):4889-96
references.pmid: 1537866
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5419-24
references.pmid: 12697904
references.citation: Nat Rev Mol Cell Biol. 2002 Apr;3(4):267-77
references.pmid: 11994746
references.citation: Mol Biol Cell. 2011 Nov;22(21):4108-23
references.pmid: 22039070
references.citation: Mol Biol Cell. 2003 Mar;14(3):973-86
references.pmid: 12631717
references.citation: Biochem J. 2006 Dec 15;400(3):485-91
references.pmid: 16901265
references.citation: Nature. 2001 Feb 8;409(6821):729-33
references.pmid: 11217863
references.citation: BMC Med. 2012 Nov 15;10:140
references.pmid: 23153210
references.citation: Nat Genet. 2010 Oct;42(10):864-8
references.pmid: 20818381
references.citation: Nat Genet. 2010 Feb;42(2):105-16
references.pmid: 20081858
references.citation: J Biol Chem. 2001 May 18;276(20):16904-10
references.pmid: 11278795
references.citation: J Clin Invest. 1997 Oct 1;100(7):1831-9
references.pmid: 9312184
references.citation: J Biol Chem. 2008 Jan 11;283(2):1064-75
references.pmid: 17989072
references.citation: Circ Res. 2005 Sep 30;97(7):682-9
references.pmid: 16141411
references.citation: Endocrinology. 1991 Aug;129(2):771-7
references.pmid: 1855475
references.citation: Science. 1989 Mar 3;243(4895):1191-4
references.pmid: 2466336
references.citation: Diabetes. 2001 Jan;50(1):24-31
references.pmid: 11147790
references.citation: Nat Genet. 2010 Jul;42(7):579-89
references.pmid: 20581827
references.citation: Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):512-6
references.pmid: 8421683
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12391-6
references.pmid: 11675488
references.citation: Lipids. 2009 Jun;44(6):477-87
references.pmid: 19440746
references.citation: J Biol Chem. 1991 Jun 25;266(18):11726-31
references.pmid: 2050674
references.citation: Front Biosci. 2003 May 01;8:s410-20
references.pmid: 12700100
references.citation: Hum Mol Genet. 2011 Jan 15;20(2):312-21
references.pmid: 21036943
references.citation: Mol Cell Biol. 2002 Aug;22(16):5989-99
references.pmid: 12138207