title: 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.forename: Spyridon
authors.initials: S
authors.lastname: Theofilopoulos
authors.forename: William J
authors.initials: WJ
authors.lastname: Griffiths
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crick
authors.forename: Shanzheng
authors.initials: S
authors.lastname: Yang
authors.forename: Anna
authors.initials: A
authors.lastname: Meljon
authors.forename: Michael
authors.initials: M
authors.lastname: Ogundare
authors.forename: Satish Srinivas
authors.initials: SS
authors.lastname: Kitambi
authors.forename: Andrew
authors.initials: A
authors.lastname: Lockhart
authors.forename: Karin
authors.initials: K
authors.lastname: Tuschl
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Morris
authors.forename: Adelaida
authors.initials: A
authors.lastname: Martinez
authors.forename: M Ashwin
authors.initials: MA
authors.lastname: Reddy
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Maria T
authors.initials: MT
authors.lastname: Bassi
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Mizuochi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nittono
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Michele
authors.forename: Rosa
authors.initials: R
authors.lastname: Carbone
authors.forename: Chiara
authors.initials: C
authors.lastname: Criscuolo
authors.forename: Joyce L
authors.initials: JL
authors.lastname: Yau
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Sailer
authors.forename: Jens
authors.initials: J
authors.lastname: Kuhle
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fraidakis
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Patrik
authors.initials: P
authors.lastname: Ernfors
authors.forename: Jan
authors.initials: J
authors.lastname: Sjövall
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D002782:Cholestenes / Q000097:blood / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000502:physiology*; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D020336:Paraparesis, Spastic / Q000097:blood / Q000134:cerebrospinal fluid; D014157:Transcription Factors / Q000378:metabolism; D019294:Xanthomatosis, Cerebrotendinous / Q000097:blood / Q000134:cerebrospinal fluid; D015027:Zebrafish
chemical_list: D002782:Cholestenes; D060850:LIM-Homeodomain Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D014157:Transcription Factors; C514718:cholestenoic acid; C063843:insulin gene enhancer binding protein Isl-1