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Identification of Cholestenoic acids that Regulate Motor Neuron Survival via Liver X Receptors

Theofilopoulos, Spyrido, Griffiths, William, Crick, Peter, Yang, Shanzheng, Meljon, Anna, Ogundare, Michael, Kitambi, Satish, Lockhart, Andrew, Tuschl, Karin, Clayton, Peter, Morris, Andrew, Martinez, Adelaida, Reddy, Ashwin, Martinuzzi, Andrea, Bassi, Maria, Honda, Akira, Mizuochi, Tatsuki, Kimura, Akihiro, Nittono, Hiroshi, De Michele, Guiseppe, Carbone, Rosa, Criscuolo, Chiara, Yau, Joyce, Seckl, Jonathan, Schüle, Rebecca, Schöls, Ludger, Sailer, Andreas, Kuhle, Jens, Fraidakis, Matthew, Gustafsson, Jan-Ake, Steffensen, Knut, Björkhem, Ingemar, Ernfors, Patrik, Sjövall, Jan, Arenas, Ernest and Wang, Yuqin (2014) Identification of Cholestenoic acids that Regulate Motor Neuron Survival via Liver X Receptors. Journal of Clinical Investigation, 124 (11). pp. 4829-4842.


Cholestenoic acids are intermediates in metabolism of cholesterol to bile acids and their biosynthetic enzymes are expressed in the mammalian CNS. Here we describe the cholestenoic acid profile of mammalian cerebrospinal fluid and show that specific cholestenoic acids, including 3β,7α-dihydroxycholest-5-en-26-oic (3β,7α-diHCA) and 3β-hydroxy-7-oxocholest-5-en-26-oic acids (3βH,7O-CA), activate the liver X receptors (Lxrs), enhance Islet-1 expression and protein levels in zebrafish in vivo, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. Mechanistically, while 3β,7α-diHCA promoted motor neuron survival in an Lxr-dependent manner, 3βH,7O-CA promoted maturation of precursors into Islet1+ cells. Surprisingly, a weak Lxr ligand, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA), caused motor neuron cell loss in vivo. Mutations in CYP7B1 or CYP27A1, two enzymes involved in cholestenoic acid metabolism, result in two different neurological diseases hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. The former disease is characterized by spastic paresis and similar symptoms may sometimes occur also in some CTX patients. 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 in plasma. Combined, our results show that specific cholestenoic acids selectively work on motor neurons, via Lxr, to regulate the balance between survival and death. These findings suggest that efforts aimed at restoring the balance between toxic and pro-survival Lxr ligands, such as administration of 3β,7α-diHCA, can lead to potential treatments for motor neuron degeneration.

Item Type: Article
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12