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Cholestenoic acids regulate motor neuron survival via liver X receptors
Spyridon Theofilopoulos, … , Ernest Arenas, Yuqin Wang
Spyridon Theofilopoulos, … , Ernest Arenas, Yuqin Wang
Published October 1, 2014
Citation Information: J Clin Invest. 2014;124(11):4829-4842. https://doi.org/10.1172/JCI68506.
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Research Article Neuroscience Article has an altmetric score of 29

Cholestenoic acids regulate motor neuron survival via liver X receptors

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Abstract

Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3β-hydroxy-7-oxocholest-5-en-26-oic acid (3βH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3β,7α-diHCA and 3βH,7O-CA, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3β-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3β,7α-diHCA. Moreover, 3β,7α-diHCA prevented the loss of motor neurons induced by 3β-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.

Authors

Spyridon Theofilopoulos, William J. Griffiths, Peter J. Crick, Shanzheng Yang, Anna Meljon, Michael Ogundare, Satish Srinivas Kitambi, Andrew Lockhart, Karin Tuschl, Peter T. Clayton, Andrew A. Morris, Adelaida Martinez, M. Ashwin Reddy, Andrea Martinuzzi, Maria T. Bassi, Akira Honda, Tatsuki Mizuochi, Akihiko Kimura, Hiroshi Nittono, Giuseppe De Michele, Rosa Carbone, Chiara Criscuolo, Joyce L. Yau, Jonathan R. Seckl, Rebecca Schüle, Ludger Schöls, Andreas W. Sailer, Jens Kuhle, Matthew J. Fraidakis, Jan-Åke Gustafsson, Knut R. Steffensen, Ingemar Björkhem, Patrik Ernfors, Jan Sjövall, Ernest Arenas, Yuqin Wang

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Figure 3

Effects of cholestenoic acids on zebrafish motor neurons.

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Effects of cholestenoic acids on zebrafish motor neurons.
Tg[isl1:GFP] e...
Tg[isl1:GFP] embryos were incubated with 10 μM test compound or vehicle added to medium, and the medium was replaced every 12 hours with fresh solution (containing test compound or vehicle). Immunocytochemistry was performed using an anti-GFP antibody at 48 hpf. (A) Dorsal (top) and dorsolateral (bottom) views of the head/upper back region of embryos treated with vehicle, 3β,7α-diHCA, or 3βH,7O-CA. Arrows indicate loci III, IV, V, VII, and X (37), which are evolutionarily homologous to the cranial nerves in humans (40). Locus III contains the oculomotor neurons, locus IV the trochlear neurons, locus V the trigeminal motor neurons, locus VII the facial motor neurons, and locus X the cell bodies of the vagus nerve. Scale bar: 50 μm. (B) Quantification of islet-1–GFP signal intensity in the different loci (n = 4). 24,25-EC was used as a positive control. (C and D) mRNA levels of (C) isl1 and (D) abca1 after treatment with the indicated compounds. Data are mean ± SEM (n = 3). *P < 0.05, **P < 0.01 vs. respective vehicle, Mann-Whitney test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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