ArticleThe Journal of clinical investigation2014
Cholestenoic acids regulate motor neuron survival via liver X receptors.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 110 citations in OpenAlex.
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- Treatment of Inborn Errors by Product Replacement: The Example of Inborn Errors of Bile Acid Synthesis.Journal of inherited metabolic disease · 2025Review
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- Inhibition of 7α,26-dihydroxycholesterol biosynthesis promotes midbrain dopaminergic neuron development.iScience · 2024Article
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- Characterization of Postprandial Bile Acid Profiles and Glucose Metabolism in Cerebrotendinous Xanthomatosis.Nutrients · 2023Article
- Amyotrophic lateral sclerosis: translating genetic discoveries into therapies.Nature reviews. Genetics · 2023Review
- Untargeted Metabolomic Analysis of Sjögren-Larsson Syndrome Reveals a Distinctive Pattern of Multiple Disrupted Biochemical Pathways.Metabolites · 2023Article
- HSD3B1 is an oxysterol 3β-hydroxysteroid dehydrogenase in human placenta.Open biology · 2023Article
- Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients.Orphanet journal of rare diseases · 2023Article
- Cholesterol metabolism: from lipidomics to immunology.Journal of lipid research · 2022Review
- Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS.Nature neuroscience · 2021Article
- 2-Hydroxypropyl-β-cyclodextrin reduces retinal cholesterol in wild-type and Cyp27a1British journal of pharmacology · 2021Article
- Cholesterol metabolism pathways - are the intermediates more important than the products?The FEBS journal · 2021Review
- Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.The Journal of steroid biochemistry and molecular biology · 2021Article
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36 authors at 15 institutions in 8 countries.
Funding
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.
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