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TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis

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Title: TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis
Authors: Owen, DRJ
Fan, J
Campioli, E
Venugopal, S
Midzak, A
Daly, E
Harlay, A
Issop, L
Libri, V
Kalogiannopoulou, D
Oliver, E
Gallego-Colon, E
Colasanti, A
Huson, L
Rabiner, EA
Suppiah, P
Essagian, C
Matthews, PM
Papadopoulos, V
Item Type: Journal Article
Abstract: The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.
Issue Date: 21-Nov-2017
Date of Acceptance: 25-Oct-2017
URI: http://hdl.handle.net/10044/1/52491
DOI: https://dx.doi.org/10.1042/BCJ20170648
ISSN: 1470-8728
Publisher: Portland Press
Start Page: 3985
End Page: 3999
Journal / Book Title: Biochemical Journal
Volume: 474
Issue: 23
Copyright Statement: © 2017 The Author(s) https://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
Sponsor/Funder: The Academy of Medical Sciences
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: n/a
MR/N008219/1
MR/N026934/1
Keywords: adrenal
cholesterol transport
gonads
lipid droplets
steroids
translocator protein
Adolescent
Adrenocorticotropic Hormone
Adult
Animals
Base Sequence
Carrier Proteins
Cholesterol Esters
Chorionic Gonadotropin
Cloning, Molecular
Corticosterone
Embryo, Mammalian
Escherichia coli
Gene Expression
Humans
Hydrocortisone
Male
Plasmids
Polymorphism, Single Nucleotide
Pregnanolone
Rats
Rats, Transgenic
Receptors, GABA
Receptors, GABA-A
Recombinant Proteins
Testosterone
Zinc Fingers
Zygote
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Biochemistry & Molecular Biology
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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