Importance of γ-secretase in the regulation of liver X receptor and cellular lipid metabolism.
Alzheimer Disease
/ genetics
Amyloid Precursor Protein Secretases
/ antagonists & inhibitors
Animals
Astrocytes
/ metabolism
Brain
/ metabolism
Cell Line, Tumor
Cholesterol Esters
/ metabolism
Diamines
/ pharmacology
Fibroblasts
/ metabolism
Gene Deletion
Glycerides
/ metabolism
Homeostasis
/ drug effects
Humans
Lipid Droplets
/ metabolism
Liver X Receptors
/ metabolism
Mice
Mice, Knockout
Presenilins
/ deficiency
Signal Transduction
/ drug effects
Thiazoles
/ pharmacology
Transfection
Up-Regulation
/ drug effects
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
08
08
2019
revised:
16
04
2020
accepted:
17
04
2020
entrez:
2
5
2020
pubmed:
2
5
2020
medline:
8
7
2021
Statut:
epublish
Résumé
Presenilins (PS) are the catalytic components of γ-secretase complexes that mediate intramembrane proteolysis. Mutations in the PS genes are a major cause of familial early-onset Alzheimer disease and affect the cleavage of the amyloid precursor protein, thereby altering the production of the amyloid β-peptide. However, multiple additional protein substrates have been identified, suggesting pleiotropic functions of γ-secretase. Here, we demonstrate that inhibition of γ-secretase causes dysregulation of cellular lipid homeostasis, including up-regulation of liver X receptors, and complex changes in the cellular lipid composition. Genetic and pharmacological inhibition of γsecretase leads to strong accumulation of cytoplasmic lipid droplets, associated with increased levels of acylglycerols, but lowered cholesteryl esters. Furthermore, accumulation of lipid droplets was augmented by increasing levels of amyloid precursor protein C-terminal fragments, indicating a critical involvement of this γ-secretase substrate. Together, these data provide a mechanism that functionally connects γ-secretase activity to cellular lipid metabolism. These effects were also observed in human astrocytic cells, indicating an important function of γ-secretase in cells critical for lipid homeostasis in the brain.
Identifiants
pubmed: 32354700
pii: 3/6/e201900521
doi: 10.26508/lsa.201900521
pmc: PMC7195048
pii:
doi:
Substances chimiques
24-diamino-5-phenylthiazole
0
Cholesterol Esters
0
Diamines
0
Glycerides
0
Liver X Receptors
0
Presenilins
0
Thiazoles
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2020 Gutierrez et al.
Références
Cell Stem Cell. 2019 Mar 7;24(3):363-375.e9
pubmed: 30686764
EMBO Mol Med. 2013 Apr;5(4):608-25
pubmed: 23554170
Science. 2003 Oct 31;302(5646):822-6
pubmed: 14593167
EMBO J. 2018 Jun 15;37(12):
pubmed: 29789390
J Biol Chem. 2016 Jun 10;291(24):12821-37
pubmed: 27059953
Prog Lipid Res. 2010 Oct;49(4):343-52
pubmed: 20363253
Cell. 2016 Jun 30;166(1):193-208
pubmed: 27293189
Biol Pharm Bull. 2011;34(4):453-61
pubmed: 21467629
EMBO J. 2006 Mar 22;25(6):1242-52
pubmed: 16511561
Biochim Biophys Acta. 2013 Dec;1828(12):2898-907
pubmed: 23791707
Cell. 2007 Oct 19;131(2):215-21
pubmed: 17956719
J Neurosci. 2011 May 11;31(19):7049-59
pubmed: 21562267
Cell Signal. 2016 Jan;28(1):1-11
pubmed: 26498858
Nat Rev Neurosci. 2011 May;12(5):284-96
pubmed: 21448224
Cell Rep. 2016 Oct 11;17(3):759-773
pubmed: 27732852
Biochem Soc Trans. 2013 Dec;41(6):1495-502
pubmed: 24256243
J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Apr 15;957:116-22
pubmed: 24674990
Cells. 2019 Mar 01;8(3):
pubmed: 30823664
Endocr Rev. 2012 Oct;33(5):715-46
pubmed: 22766509
Mol Neurodegener. 2013 Oct 22;8:34
pubmed: 24148205
J Biol Chem. 2013 Nov 15;288(46):33027-36
pubmed: 24078628
N Engl J Med. 2013 Oct 17;369(16):1569-70
pubmed: 24143816
J Biol Chem. 2016 Feb 26;291(9):4334-41
pubmed: 26694609
Trends Cell Biol. 2016 Jul;26(7):535-546
pubmed: 26995697
Nat Rev Neurosci. 2016 Apr;17(4):201-7
pubmed: 26911435
Neuron. 2007 Oct 4;56(1):66-78
pubmed: 17920016
Curr Biol. 2018 Mar 19;28(6):915-926.e9
pubmed: 29526591
J Biol Chem. 2013 Jul 19;288(29):20868-82
pubmed: 23723072
Biol Chem. 2017 Apr 1;398(4):441-453
pubmed: 27845877
J Neurosci. 2002 Mar 1;22(5):1679-89
pubmed: 11880497
J Neurosci. 2012 Jun 20;32(25):8633-48
pubmed: 22723704
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19524-9
pubmed: 17158800
Arch Pharm Res. 2006 Oct;29(10):884-9
pubmed: 17121184
Cell Metab. 2012 Oct 3;16(4):414-9
pubmed: 23000402
J Biol Chem. 2003 Jul 25;278(30):27688-94
pubmed: 12754201
Nat Rev Drug Discov. 2014 Jun;13(6):433-44
pubmed: 24833295
Ann Neurol. 2002 Oct;52(4):448-57
pubmed: 12325074
Mini Rev Med Chem. 2003 Sep;3(6):576-84
pubmed: 12871160
Annu Rev Pharmacol Toxicol. 2015;55:419-37
pubmed: 25292430
Cold Spring Harb Perspect Med. 2012 Oct 01;2(10):
pubmed: 23028126
Oncogene. 2019 Jan;38(2):151-163
pubmed: 30166589
Traffic. 2008 Mar;9(3):338-52
pubmed: 18088320
Prog Lipid Res. 2011 Oct;50(4):357-71
pubmed: 21741992
ACS Chem Biol. 2012 Dec 21;7(12):2004-11
pubmed: 22999348
Neuron. 2004 Oct 14;44(2):227-38
pubmed: 15473963
J Alzheimers Dis. 2011;25(1):3-28
pubmed: 21335653
Neurotherapeutics. 2014 Oct;11(4):732-7
pubmed: 25113539
Science. 1993 Aug 13;261(5123):921-3
pubmed: 8346443
Annu Rev Cell Dev Biol. 2017 Oct 6;33:491-510
pubmed: 28793795
Cancer Lett. 2019 Oct 1;461:123-131
pubmed: 31326555
J Neurochem. 2017 Nov;143(4):445-454
pubmed: 28940294
EMBO J. 2012 Nov 5;31(21):4106-23
pubmed: 22892566
Science. 2012 Jun 1;336(6085):1168-71
pubmed: 22654059
Annu Rev Cell Dev Biol. 2010;26:235-60
pubmed: 20604710
Traffic. 2006 Apr;7(4):408-15
pubmed: 16536739
Biol Psychiatry. 2015 Jan 1;77(1):43-51
pubmed: 24951455
J Neurosci. 2003 Jul 2;23(13):5645-9
pubmed: 12843267
J Biol Chem. 2018 Jul 20;293(29):11341-11357
pubmed: 29858247
Mol Neurobiol. 2016 Jul;53(5):3428-3438
pubmed: 26081153
Neuron. 2020 Mar 4;105(5):837-854.e9
pubmed: 31902528
Curr Alzheimer Res. 2019;16(5):453-457
pubmed: 30907322
Mol Psychiatry. 2016 May;21(5):707-16
pubmed: 26194181
N Engl J Med. 2013 Jan 10;368(2):107-16
pubmed: 23150908
J Steroid Biochem Mol Biol. 2019 Jun;190:1-10
pubmed: 30885834
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2070-5
pubmed: 14970312
Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:237-261
pubmed: 30208281
Neurochem Res. 2011 Oct;36(10):1910-21
pubmed: 21630010
Trends Mol Med. 2007 Aug;13(8):337-44
pubmed: 17644432
J Alzheimers Dis. 2018;61(1):1-15
pubmed: 29103038
J Biol Chem. 2003 Apr 11;278(15):13244-56
pubmed: 12547833
Nat Cell Biol. 2001 Oct;3(10):905-12
pubmed: 11584272
Nat Cell Biol. 2005 Nov;7(11):1118-23
pubmed: 16227967
J Biol Chem. 2019 Feb 1;294(5):1706-1709
pubmed: 30710017
Pharmacol Ther. 2015 Mar;147:80-90
pubmed: 25448038
J Biol Chem. 2005 Feb 25;280(8):6663-8
pubmed: 15613480
J Cell Biol. 2012 Jul 9;198(1):23-35
pubmed: 22753898
J Biol Chem. 2012 Jan 20;287(4):2678-88
pubmed: 22134919
J Neurosci. 2014 Oct 22;34(43):14484-501
pubmed: 25339759
J Endocrinol. 2010 Mar;204(3):233-40
pubmed: 19837721
EMBO Rep. 2014 Oct;15(10):1036-52
pubmed: 25223281
Mol Neurodegener. 2007 Oct 22;2:20
pubmed: 17953774
J Neurosci. 2008 Nov 12;28(46):12097-106
pubmed: 19005074
J Biol Chem. 2002 Nov 22;277(47):44754-9
pubmed: 12223485
J Lipid Res. 2014 Mar;55(3):583-91
pubmed: 24334219
FASEB J. 2006 Jun;20(8):1176-8
pubmed: 16645046
Sci Transl Med. 2014 Jul 2;6(243):243ra86
pubmed: 24990881
Mol Med Rep. 2015 Oct;12(4):6037-42
pubmed: 26252415
Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1869-74
pubmed: 23302688
J Neurochem. 2006 Feb;96(3):732-42
pubmed: 16405513
Traffic. 2009 Nov;10(11):1579-84
pubmed: 19765264
J Neuroinflammation. 2016 Jan 20;13:17
pubmed: 26792193
Arterioscler Thromb Vasc Biol. 2016 Jul;36(7):1305-15
pubmed: 27174096
PLoS One. 2019 Jan 25;14(1):e0210535
pubmed: 30682043
Mol Cell. 2001 Jan;7(1):161-71
pubmed: 11172721
Cell. 2010 Jun 25;141(7):1146-58
pubmed: 20541250
Biochim Biophys Acta. 2013 Dec;1828(12):2815-27
pubmed: 24099003
Trends Endocrinol Metab. 2016 Jun;27(6):404-414
pubmed: 27113081
Nat Rev Mol Cell Biol. 2004 Jun;5(6):499-504
pubmed: 15173829
Glia. 2017 Jul;65(7):1103-1118
pubmed: 28370426
Biochim Biophys Acta Mol Cell Res. 2017 Sep;1864(9):1459-1468
pubmed: 28390906
J Neurochem. 2019 Oct 14;:
pubmed: 31608980
J Neurochem. 2007 May;101(4):929-36
pubmed: 17472585