Cholestenoic acids regulate motor neuron survival via liver X receptors

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 MicheleRosa 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

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)4829-42
Number of pages14
JournalThe Journal of clinical investigation
Issue number11
Publication statusPublished - Nov 2014


  • Animals
  • Cell Survival
  • Cells, Cultured
  • Cholestenes/blood
  • Female
  • Humans
  • LIM-Homeodomain Proteins/metabolism
  • Liver X Receptors
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Neurons/physiology
  • Orphan Nuclear Receptors/metabolism
  • Paraparesis, Spastic/blood
  • Transcription Factors/metabolism
  • Xanthomatosis, Cerebrotendinous/blood
  • Zebrafish

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