Alterations in endo-lysosomal function induce similar hepatic lipid profiles in rodent models of drug-induced phospholipidosis and Sandhoff disease
Author(s)
Lecommandeur, Emmanuelle
Baker, David
Cox, Timothy M
Nicholls, Andrew W
Griffin, Julian L
Type
Journal Article
Abstract
Drug-induced phospholipidosis (DIPL) is characterized by an increase in the phospholipid content of the cell and the accumulation of drugs and lipids inside the lysosomes of affected tissues, including in the liver. Although of uncertain pathological significance for patients, the condition remains a major impediment for the clinical development of new drugs. Human Sandhoff disease (SD) is caused by inherited defects of the β subunit of lysosomal β-hexosaminidases (Hex) A and B, leading to a large array of symptoms, including neurodegeneration and ultimately death by the age of 4 in its most common form. The substrates of Hex A and B, gangliosides GM2 and GA2, accumulate inside the lysosomes of the CNS and in peripheral organs. Given that both DIPL and SD are associated with lysosomes and lipid metabolism in general, we measured the hepatic lipid profiles in rodent models of these two conditions using untargeted LC/MS to examine potential commonalities. Both model systems shared a number of perturbed lipid pathways, notably those involving metabolism of cholesteryl esters, lysophosphatidylcholines, bis(monoacylglycero)phosphates, and ceramides. We report here profound alterations in lipid metabolism in the SD liver. In addition, DIPL induced a wide range of lipid changes not previously observed in the liver, highlighting similarities with those detected in the model of SD and raising concerns that these lipid changes may be associated with underlying pathology associated with lysosomal storage disorders.
Date Issued
2017-07-01
Date Acceptance
2017-04-01
Citation
Journal of Lipid Research, 2017, 58 (7), pp.1306-1314
ISSN
0022-2275
Publisher
American Society for Biochemistry and Molecular Biology
Start Page
1306
End Page
1314
Journal / Book Title
Journal of Lipid Research
Volume
58
Issue
7
Copyright Statement
© 2017 by the American Society for Biochemistry and Molecular Biology, Inc.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000404576500004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
ceramides
lipidomics
lysophospholipid
lysosome
mass spectrometry
storage diseases
toxicology
CATIONIC AMPHIPHILIC DRUGS
CERAMIDE SYNTHASE 2
TAY-SACHS
SPHINGOLIPID METABOLISM
MOUSE MODELS
BETA-HEXOSAMINIDASE
ACTIVATOR PROTEINS
STORAGE DISORDER
CHAIN LENGTH
TRAFFIC JAM
Publication Status
Published
Date Publish Online
2017-04-04