Cholestenoic acids regulate motor neuron survival via liver X receptors
Spyridon Theofilopoulos, … , Ernest Arenas, Yuqin Wang
Spyridon Theofilopoulos, … , Ernest Arenas, Yuqin Wang
Published November 3, 2014; First published October 1, 2014
Citation Information: J Clin Invest. 2014;124(11):4829-4842. https://doi.org/10.1172/JCI68506.
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Categories: Research Article Neuroscience

Cholestenoic acids regulate motor neuron survival via liver X receptors

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 1

Biosynthesis of cholestenoic acids in brain and levels of cholestenoic acids in the circulation and CSF.

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Biosynthesis of cholestenoic acids in brain and levels of cholestenoic a...
(A) Suggested metabolic pathway for the biosynthesis of 3β-HCA, 3β,7α-diHCA, 3β,7β-diHCA, and 7αH,3O-CA. Sterols are abbreviated according to cholesterol (C), cholest-4-en-3-one (CO), and cholesten-26-oic acid (CA) structures; numbers (with Greek letters) indicate the location of hydroxy (H) and oxo (O) groups. The enzymes in the pathway are indicated. With the exception of the epimerase, each enzyme is known to be expressed in brain. Enzyme defects in CTX and SPG5 are depicted by solid bars across arrows. Metabolites that are toxic toward neurons (red) or neuroprotective (green) are indicated. (B–E) Levels of (B) 26-HC, (C) 3β-HCA, (D) 3β,7α-diHCA, and (E) 3β,7β-diHCA in plasma/serum from control subjects (Cn; n = 50), CTX patients (n = 4), SPG5 patients (Sp; n = 9), SPG5 carriers (Sc; n = 3) and infants with O7AHD (7a; n = 3). (F–I) Levels of (F) 26-HC, (G) 3β-HCA, (H) 3β,7α-diHCA, and (I) 3β,7β-diHCA in CSF from control subjects (n = 18), SPG5 patients (n = 3), and SPG5 carriers (n = 2). Measurements were made by LC-ESI-MS (see Supplemental Tables 1 and 2). *P < 0.05, **P < 0.01, ***P < 0.001 vs. control, Dunnett T3 test.